Substituted 6-azabenzimidazole compounds

ABSTRACT

The present disclosure relates generally to certain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/753,339, filed Oct. 31, 2018 and U.S. Provisional Application No.62/868,550, filed Jun. 28, 2019, each of which is incorporated herein inits entirety for all purposes.

FIELD

This disclosure relates generally to certain 6-azabenzimidazolecompounds, pharmaceutical compositions comprising said compounds, andmethods of making and using said compounds and pharmaceuticalcompositions.

BACKGROUND

Immuno-oncology is a burgeoning area of cancer research, highlighted byinhibitor antibodies against the immune checkpoint receptors CTLA4, PD-1and PD-L1. Targeted disruption of these checkpoint pathways releases theimmune cell from key regulatory pathways, allowing for a boost in theimmune response against cancer cells. Current therapies utilizing theseantibodies are highlighted by both significant and durable response tomany different cancers but also by low overall response rates (<25%).Understanding and improving these response rates is a formidable goal,and the combination of checkpoint blockade with other immune activatingagents or cell based therapies could provide an inroad to expand uponpatient responses.

Hematopoietic progenitor kinase 1 (HPK1), a STE20 ser/thr kinase fromthe germinal center family of kinases, regulates the function of diverseimmune populations including T cells, B cells, and dendritic cells (Huet al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In T cells,HPK1 serves as a negative regulator of T cell receptor (TCR) signaling(Liou et al., Immunity 2000; Sauer et al., JBC 2001) by phosphorylatingSLP76 on serine 376, which induces the association of SLP76 with 14-3-3proteins, and leads to the disassociation of the signaling complex (DiBartolo et al., JEM 2007). Further supporting the role of HPK1 as anegative regulator of TCR signaling, murine HPK1 deficient T cells orHPK1 kinase inactive mutant T cells have enhanced ERK 1/2 activation andeffector cytokine secretion upon TCR activation compared to theirwild-type counterparts (Shui et al., Nat Immunol 2007; Hernandez et al.,Cell Reports 2018). Accordingly, a small molecule inhibitor of HPK1could provide a novel way to enhance anti-tumor immunity and alsoprovide a way to increase the response to checkpoint receptor blockade.

SUMMARY

In one aspect, provided herein is a compound of Formula I,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the        other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein each        C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH and halogen, or    -   R¹ and R² together with the carbon to which they are attached        form a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic        heterocyclyl having 1 or 2 heteroatoms independently selected        from N, O, and S, wherein the C₃₋₇ monocyclic cycloalkyl and the        4-6 membered monocyclic heterocyclyl are each optionally        substituted with one R¹¹ and are each optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy, or    -   R¹ and R² together form ═O;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) —S(O)₂C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) H,        -   ii) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃            alkoxy, wherein the C₁₋₃ alkyl is optionally substituted            with 1-3 groups independently selected from —OH, halogen,            and C₁₋₃ alkoxy,        -   iii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   v) —NH₂,        -   vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   viii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   ix) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from        -   a) —CN,        -   b) —OH,        -   c) halogen,        -   d) C₁₋₃ alkoxy,        -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —CN, —OH, halogen,            C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   f) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and        -   g) —OC(O)C₁₋₆ alkyl optionally substituted with one —OH;    -   R³ and R¹³ are each H, or    -   R³ and R¹³ together form ═O;    -   L¹ is a cyclobutylene optionally substituted with 1-6 groups        independently selected from —OH, halogen, C₁-3 alkyl, and C₁₋₃        alkoxy;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and            -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃                alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) —CN,        -   ii) a halogen,        -   iii) —OH,        -   iv) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   vi) —COOH, or        -   vii) —C(O)N(R²²)₂, wherein each R²² is independently H or            C₁₋₆ alkyl;    -   X¹ is N or CR¹⁷;    -   R⁴, R⁵, R⁶, R¹⁰ and R¹⁷ are each independently H, halogen, C₁₋₃        alkyl, or C₁₋₃ alkoxy;    -   R⁷ is        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   Z is —O—, —C(R⁸)₂—, or —NR⁸—;    -   each R⁸ is independently H or C₁₋₃ alkyl;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) —NH₂,        -   v) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vi) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same            or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vii) —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   viii) —S(O)₂C₁₋₆ alkyl,        -   ix) —S(O)₂N(R²³)₂, wherein each R²³ is independently H or            C₁₋₆ alkyl,        -   x) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —OH,            -   b) halogen,            -   c) C₁₋₃ alkoxy,            -   d) C₃₋₇ monocyclic cycloalkyl,            -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from oxo and C₁₋₃ alkyl, and            -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl,        -   xi) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   xii) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xiii) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xiv) —COOH,        -   xv) —C(O)N(R¹⁹)₂, or        -   xvi) —C₁₋₃ alkylC(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂ or —C₁₋₃ alkylC(O)N(R¹⁹)₂; and    -   each R¹⁹ is independently        -   i) H,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl,        -   iv) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein the C₁₋₆ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or        -   v) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-6 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient or carrier. Insome embodiments, the pharmaceutical compositions comprise atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In one aspect, the present disclosure provides methods of inhibitingHPK1 activity in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa,IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treating adisease or disorder associated with increased HPK1 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of increasingT-cell activation in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa,IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treatingcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of inhibiting thegrowth or proliferation of cancer cells in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula I, II,Ia, Ib, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition provided herein.

DETAILED DESCRIPTION I. Definitions

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

As used in the present disclosure, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named. A solid line comingout of the center of a ring indicates that the point of attachment for asubstituent on the ring can be at any ring atom. For example, R^(a) inthe below structure can be attached to any of the five carbon ring atomsor R^(a) can replace the hydrogen attached to the nitrogen ring atom:

The prefix “C_(u),” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings,wherein x and y are numerical ranges, such as “3 to 12-memberedheterocyclyl”, refers to a ring containing x-y atoms (e.g., 3-12), ofwhich up to 80% may be heteroatoms, such as N, O, S, P, and theremaining atoms are carbon.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, or alkylyl group, an “arylene” group oran “arylenyl” group, or arylyl group, respectively.

“A compound disclosed herein” or “a compound of the present disclosure”or “a compound provided herein” or “a compound described herein” refersto the compounds of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc. Alsoincluded are the specific compounds of Examples 1 to 297.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, the term “about X” includesdescription of “X”.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.,—(CH₂)₃CH₃), sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e.,—CH₂CH(CH₃)₂) and tert-butyl (i.e., —C(CH₃)₃); and “propyl” includesn-propyl (i.e., —(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxy”refers to an alkoxy group as defined above, wherein one or more hydrogenatoms are replaced by a halogen.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(═O)NR^(Y)R^(Z) and an “N-amido” group which refers to the group—NR^(Y)C(═O)R^(Z), wherein R^(Y) and R^(Z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl,heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionallysubstituted.

“Amino” refers to the group —NR^(Y)R^(Z) wherein R^(Y) and R^(Z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of whichmay be optionally substituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as alkylenyl group, analkylenyl group containing one or two heteroatoms, or a singleheteroatom. Quinuclidinyl and admantanyl are examples of bridged ringsystems.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 carbon ring atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 ringheteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen, and sulfur. Examples of heteroaryl groups includepyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to anon-aromatic cyclic alkyl group, with one or more ring heteroatomsindependently selected from nitrogen, oxygen and sulfur. As used herein,“heterocyclyl” or “heterocyclic ring” or “heterocycle” refer to ringsthat are saturated or partially saturated unless otherwise indicated,e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to rings that are partially saturated wherespecified. The term “heterocyclyl” or “heterocyclic ring” or“heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclylgroup having at least one double bond). A heterocyclyl may be a singlering or multiple rings wherein the multiple rings may be fused, bridged,or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 carbon ring atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 carbon ring atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 carbon ring atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 carbon ringatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 carbon ring atoms (i.e., C₃₋₈heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“bridged-heterocyclyl” refers to a four- to ten-membered cyclic moietyconnected at two non-adjacent atoms of the heterocyclyl with one or more(e.g., 1 or 2) four- to ten-membered cyclic moiety having at least oneheteroatom where each heteroatom is independently selected fromnitrogen, oxygen, and sulfur. As used herein, “bridged-heterocyclyl”includes bicyclic and tricyclic ring systems. Also as used herein, theterm “spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl include bicyclic andtricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. As usedherein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring”are used interchangeably. In some embodiments, a heterocyclyl issubstituted with an oxo group.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R^(c), where R^(c) is alkyl,haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples ofsulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, andtoluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” means that any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, amino,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one ormore substituents including alkyl, amino, haloalkyl, heterocyclyl,cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or moresubstituents including halo, alkyl, amino, haloalkyl, cycloalkyl,heterocyclyl, heteroaryl, alkoxy, and cyano; “substituted heteroaryl”refers to an heteroaryl group having one or more substituents includinghalo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to agroup —S(O)₂R, in which R is substituted with one or more substituentsincluding alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Inother embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is unsubstituted.

In some embodiments, a substituted cycloalkyl, a substitutedheterocyclyl, a substituted aryl, and/or a substituted heteroarylincludes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl thathas a substituent on the ring atom to which the cycloalkyl,heterocyclyl, aryl, and/or heteroaryl is attached to the rest of thecompound. For example, in the below moiety, the cyclopropyl issubstituted with a methyl group:

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)-for amino acids. Thepresent disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Wherecompounds are represented in their chiral form, it is understood thatthe embodiment encompasses, but is not limited to, the specificdiastereomerically or enantiomerically enriched form. Where chirality isnot specified but is present, it is understood that the embodiment isdirected to either the specific diastereomerically or enantiomericallyenriched form; or a racemic or scalemic mixture of such compound(s). Asused herein, “scalemic mixture” is a mixture of stereoisomers at a ratioother than 1:1.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any compounds provided herein.

Some of the compounds provided herein exist as tautomeric isomers.Tautomeric isomers are in equilibrium with one another. For example,amide containing compounds may exist in equilibrium with imidic acidtautomers. Regardless of which tautomer is shown, and regardless of thenature of the equilibrium among tautomers, the compounds are understoodby one of ordinary skill in the art to comprise both amide and imidicacid tautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds provided herein are also provided.Hydrates of the compounds provided herein are also provided.

Any formula or structure provided herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ²H, ³H, ¹³C and ¹⁴C are incorporated,are also provided herein. Such isotopically labelled compounds may beuseful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The present disclosure also includes compounds of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc in which from 1 to n hydrogens attached to acarbon atom is/are replaced by deuterium, in which n is the number ofhydrogens in the molecule. Such compounds exhibit increased resistanceto metabolism and are thus useful for increasing the half-life of anycompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, whenadministered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of the presentdisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to absorption, distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life, reduceddosage requirements and/or an improvement in therapeutic index. An ¹⁸Flabeled compound may be useful for PET or SPECT studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure, any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosure,any atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,and the like. Specific examples of suitable amines include, by way ofexample only, isopropylamine, trimethyl amine, diethyl amine,tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,2-dimethylaminoethanol, piperazine, piperidine, morpholine,N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival).

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofhematopoietic progenitor kinase 1 (HPK1) activity. The therapeuticallyeffective amount may vary depending on the subject, and the disease orcondition being treated, the weight and age of the subject, the severityof the disease or condition, and the manner of administering, which canreadily be determined by one of ordinary skill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of HPK1” orvariants thereof refers to a decrease in HPK1 activity as a direct orindirect response to the presence of a compound of the presentdisclosure relative to the HPK1 activity in the absence of the compoundof the present disclosure. “Inhibition of HPK1” refers to a decrease inHPK1 activity as a direct or indirect response to the presence of acompound provided herein relative to the HPK1 activity in the absence ofthe compound provided herein. In some embodiments, the inhibition ofHPK1 activity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

II. Compounds

In one aspect, provided herein is a compound of Formula I,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the        other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein each        C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH and halogen, or    -   R¹ and R² together with the carbon to which they are attached        form a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic        heterocyclyl having 1 or 2 heteroatoms independently selected        from N, O, and S, wherein the C₃₋₇ monocyclic cycloalkyl and the        4-6 membered monocyclic heterocyclyl are each optionally        substituted with one R¹¹ and are each optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy, or    -   R¹ and R² together form ═O;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) —S(O)₂C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) H,        -   ii) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃            alkoxy, wherein the C₁₋₃ alkyl is optionally substituted            with 1-3 groups independently selected from —OH, halogen,            and C₁₋₃ alkoxy,        -   iii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   v) —NH₂,        -   vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   viii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   ix) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —CN, —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,            -   f) 4-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 4-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and                C₁₋₃ alkoxy, and            -   g) —OC(O)C₁₋₆ alkyl optionally substituted with one —OH;    -   R³ and R¹³ are each H, or    -   R³ and R¹³ together form ═O;    -   L¹ is a cyclobutylene optionally substituted with 1-6 groups        independently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃        alkoxy;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and            -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃                alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) —CN,        -   ii) a halogen,        -   iii) —OH,        -   iv) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁-3 alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   vi) —COOH, or        -   vii) —C(O)N(R²²)₂, wherein each R²² is independently H or            C₁₋₆ alkyl;    -   X¹ is N or CR¹⁷;    -   R⁴, R⁵, R⁶, R¹⁰ and R¹⁷ are each independently H, halogen, C₁₋₃        alkyl, or C₁₋₃ alkoxy;    -   R⁷ is        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁-3            alkyl, and C₁₋₃ alkoxy;    -   Z is —O—, —C(R⁸)₂—, or —NR⁸—;    -   each R⁸ is independently H or C₁-3 alkyl;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) —NH₂,        -   v) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vi) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same            or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vii) —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   viii) —S(O)₂C₁₋₆ alkyl,        -   ix) —S(O)₂N(R²³)₂, wherein each R²³ is independently H or            C₁₋₆ alkyl,        -   x) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —OH,            -   b) halogen,            -   c) C₁₋₃ alkoxy,            -   d) C₃₋₇ monocyclic cycloalkyl,            -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from oxo and C₁₋₃ alkyl, and            -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl,        -   xi) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   xii) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xiii) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xiv) —COOH,        -   xv) —C(O)N(R¹⁹)₂, or        -   xvi) —C₁₋₃ alkylC(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂ or —C₁₋₃ alkylC(O)N(R¹⁹)₂; and    -   each R¹⁹ is independently        -   i) H,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl,        -   iv) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein the C₁₋₆ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or        -   v) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-6 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments, the compound of Formula I is of Formula II,

or a pharmaceutically acceptable salt thereof,wherein

-   -   each R¹² is independently —OH, halogen, C₁₋₃ alkyl, or C₁₋₃        alkoxy; and    -   n is 0, 1, 2, 3, or 4;    -   and the remaining variables are as defined as in Formula I.

In some embodiments, the compound of Formula I or II is of Formula IIa,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II or IIa is of FormulaIIb:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, L¹ is a cyclobutylene optionally substitutedwith 1, 2, 3, 4, 5, or 6 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, or a pharmaceutically acceptable salt thereof, L¹is a cyclobutylene. In some embodiments of the compound of Formula I, ora pharmaceutically acceptable salt thereof, L¹ is a cyclobutylenesubstituted with one C₁₋₃ alkyl group. In some embodiments of thecompound of Formula I, or a pharmaceutically acceptable salt thereof, L¹is a cyclobutylene substituted with one methyl group.

In some embodiments of the compound of Formula II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R¹² is OH. In some embodimentsof the compound of Formula II, IIa, or IIb, or a pharmaceuticallyacceptable salt thereof, R¹² is halogen. In some embodiments of thecompound of Formula II, IIa, or IIb, or a pharmaceutically acceptablesalt thereof, R¹² is C₁₋₃ alkyl. In some embodiments of the compound ofFormula II, IIa, or IIb, or a pharmaceutically acceptable salt thereof,R¹² is C₁₋₃ alkoxy. In some embodiments of the compound of Formula II,IIa, or IIb, or a pharmaceutically acceptable salt thereof, R¹² ismethyl.

In some embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, n is 0, 1, 2, 3, or 4. In someembodiments of the compound of Formula II or IIa, or a pharmaceuticallyacceptable salt thereof, n is 0, 1, 2, or 3. In some embodiments of thecompound of Formula II or IIa, or a pharmaceutically acceptable saltthereof, n is 0, 1, or 2. In some embodiments of the compound of FormulaII or IIa, or a pharmaceutically acceptable salt thereof, n is 0 or 1.In some embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, n is 0. In some embodiments ofthe compound of Formula II or IIa, or a pharmaceutically acceptable saltthereof, n is 1. In some embodiments of the compound of Formula II orIIa, or a pharmaceutically acceptable salt thereof, n is 2. In someembodiments of the compound of Formula II or IIa, or a pharmaceuticallyacceptable salt thereof, n is 3. In some embodiments of the compound ofFormula II or IIa, or a pharmaceutically acceptable salt thereof, n is4.

In some embodiments of the compound of Formula II, IIa, or IIb, or apharmaceutically acceptable salt thereof, n is 1 and R¹² is C₁₋₃ alkyl.In some embodiments of the compound of Formula II, IIa, or IIb, or apharmaceutically acceptable salt thereof, n is 1 and R¹² is methyl. Insome embodiments of the compound of Formula II, IIa, or IIb, or apharmaceutically acceptable salt thereof, n is 1 and R¹² is C₁₋₃ alkyl.In some embodiments of the compound of Formula II, IIa, or IIb, or apharmaceutically acceptable salt thereof, n is 1 and R¹² is methyl.

In some embodiments of the compound of Formula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R⁴ is H. In some embodimentsof the compound of Formula I, II, IIa, or IIb, or a pharmaceuticallyacceptable salt thereof, R⁴ is halogen. In some embodiments of thecompound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptablesalt thereof, R⁴ is fluoro. In some embodiments of the compound ofFormula I, II, IIa, or IIb, or a pharmaceutically acceptable saltthereof, R⁴ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, IIa, or IIb, or a pharmaceutically acceptable saltthereof, R⁴ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R⁵ is H. In some embodimentsof the compound of Formula I, II, IIa, or IIb, or a pharmaceuticallyacceptable salt thereof, R⁵ is halogen. In some embodiments of thecompound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptablesalt thereof, R⁵ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, IIa, or IIb, or a pharmaceutically acceptable saltthereof, R⁵ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R⁶ is H. In some embodimentsof the compound of Formula I, II, IIa, or IIb, or a pharmaceuticallyacceptable salt thereof, R⁶ is halogen. In some embodiments of thecompound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptablesalt thereof, R⁶ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, IIa, or IIb, or a pharmaceutically acceptable saltthereof, R⁶ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R¹⁰ is H. In some embodimentsof the compound of Formula I, II, IIa, or IIb, or a pharmaceuticallyacceptable salt thereof, R¹⁰ is halogen. In some embodiments of thecompound of Formula I, II, IIa, or IIb, or a pharmaceutically acceptablesalt thereof, R¹⁰ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, IIa, or IIb, or a pharmaceutically acceptable saltthereof, R¹⁰ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, or IIb, or apharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶, and R¹⁰ are H.

In some embodiments, the compound of Formula I, II, or IIa is of FormulaIII,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II, IIa, IIb, and III isof Formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II, or IIa is of FormulaIII,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is —OH, halogen or C₁₋₃ alkyl, and the other of        R¹ and R² is halogen or C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₃ alkyl,        -   iii) —S(O)₂C₃₋₅ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃            alkyl is optionally substituted with 1-3 groups            independently selected from —OH, halogen, and C₁₋₃ alkoxy,        -   ii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from        -   a) —CN,        -   b) —OH,        -   c) halogen, and        -   d) C₁₋₃ alkoxy,    -   R³ and R¹³ are each H, or    -   R³ and R¹³ together form ═O;    -   n is 0 or 1;    -   R¹² is C₁₋₃ alkyl;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   g) —OH,            -   h) halogen, and            -   i) C₁₋₃ alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) a halogen,        -   ii) —OH, or        -   iii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl;    -   X¹ is N or CH;    -   R⁷ is        -   i) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   Z is —O— or NH;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy, or        -   vi) —C(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂;    -   each R¹⁹ is independently        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments, the compound of Formula I, II, IIa, IIb or III isof Formula IIIa:

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is —OH, halogen or C₁₋₃ alkyl, and the other of        R¹ and R² is halogen or C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy;    -   R¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₃ alkyl,        -   iii) —S(O)₂C₃₋₅ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃            alkyl is optionally substituted with 1-3 groups            independently selected from —OH, halogen, and C₁₋₃ alkoxy,        -   ii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from        -   a) —CN,        -   b) —OH,        -   c) halogen, and        -   d) C₁₋₃ alkoxy,    -   R³ and R¹³ are each H, or    -   R³ and R¹³ together form ═O;    -   R¹² is C₁₋₃ alkyl;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from        -   a) —OH,        -   b) halogen, and        -   c) C₁₋₃ alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) a halogen,        -   ii) —OH, or        -   iii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl;    -   X¹ is N or CH;    -   R⁷ is        -   i) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   Z is —O— or NH;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy, or        -   vi) —C(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂;    -   each R¹⁹ is independently        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁-3 alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁-3 alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III, orIIIa, or a pharmaceutically acceptable salt thereof, R³ and R¹³ togetherform ═O. In some embodiments of the compound of Formula I, II, IIa, IIb,or IIIa, or a pharmaceutically acceptable salt thereof, R³ and R¹³ areeach H.

In some embodiments of the compound of Formula I, II, IIa, IIb, III, orIIIa, or a pharmaceutically acceptable salt thereof, X¹ is CR⁷.

In some embodiments of the compound of Formula I, II, IIa, IIb, III, orIIIa, or a pharmaceutically acceptable salt thereof, R¹⁷ is H. In someembodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, ora pharmaceutically acceptable salt thereof, R¹⁷ is halogen. In someembodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, ora pharmaceutically acceptable salt thereof, R¹⁷ is C₁-3 alkyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, ora pharmaceutically acceptable salt thereof, R¹⁷ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III orIIIa, or a pharmaceutically acceptable salt thereof, X¹ is CH. In someembodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, ora pharmaceutically acceptable salt thereof, X¹ is N.

In some embodiments of the compound of Formula I, II, IIa, IIb, III, orIIIa, or a pharmaceutically acceptable salt thereof, Z is —NR⁸—. In someembodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, ora pharmaceutically acceptable salt thereof, Z is —C(R⁸)₂—.

In some embodiments of the compound of Formula I, II, IIa, IIb, III orIIIa, or a pharmaceutically acceptable salt thereof, R⁸ is H. In someembodiments of the compound of Formula I, II, IIa, IIb, III or IIIa, ora pharmaceutically acceptable salt thereof, R⁸ is C₁₋₃ alkyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III orIIIa, or a pharmaceutically acceptable salt thereof, Z is —NH—. In someembodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, ora pharmaceutically acceptable salt thereof, Z is —CH₂—. In someembodiments of the compound of Formula I, II, IIa, IIb, III, or IIIa, ora pharmaceutically acceptable salt thereof, Z is —O—.

In some embodiments of the compound of Formula I, II, IIa, IIb, III, orIIIa, or a pharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶, R¹⁰,and R¹⁷ are H. In some embodiments of the compound of Formula I, II,IIa, IIb, III or IIIa, or a pharmaceutically acceptable salt thereof,R⁴, R⁵, R⁶, and R¹⁰ are H; X¹ is CH; and Z is NH. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, or IIIa, or apharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶, and R¹⁰ are H; X¹is N; and Z is NH.

In some embodiments, the compound of Formula I, II, IIa, or III, is ofFormula IV,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II, IIa, or III, is ofFormula IV,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is —OH, halogen or C₁₋₃ alkyl, and the other of        R¹ and R² is halogen or C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₃ alkyl,        -   iii) —S(O)₂C₃₋₄ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃            alkyl is optionally substituted with 1-3 groups            independently selected from —OH, halogen, and C₁₋₃ alkoxy,        -   ii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen, and            -   d) C₁₋₃ alkoxy,    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —OH,            -   b) halogen, and            -   c) C₁₋₃ alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) a halogen,        -   ii) —OH, or        -   iii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl;    -   R⁷ is        -   i) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy, or        -   vi) —C(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂;    -   each R¹⁹ is independently        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments, the compound of Formula I, II, IIa, or III, is ofFormula IVa:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II, IIa, or III, is ofFormula IVa:

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is —OH, halogen or C₁₋₃ alkyl, and the other of        R¹ and R² is halogen or C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₃ alkyl,        -   iii) —S(O)₂C₃₋₄ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃            alkyl is optionally substituted with 1-3 groups            independently selected from —OH, halogen, and C₁₋₃ alkoxy,        -   ii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen, and            -   d) C₁₋₃ alkoxy,    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —OH,            -   b) halogen, and            -   c) C₁₋₃ alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) a halogen,        -   ii) —OH, or        -   iii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl;    -   R⁷ is        -   i) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy, or        -   vi) —C(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂;    -   each R¹⁹ is independently        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, orIIIa, is of Formula IVb or IVc:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, orIIIa, is of Formula IVb or IVc:

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is —OH, halogen or C₁₋₃ alkyl, and the other of        R¹ and R² is halogen or C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₃ alkyl,        -   iii) —S(O)₂C₃₋₄ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃            alkyl is optionally substituted with 1-3 groups            independently selected from —OH, halogen, and C₁₋₃ alkoxy,        -   ii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen, and            -   d) C₁₋₃ alkoxy,    -   R¹² is C₁₋₃ alkyl;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —OH,            -   b) halogen, and            -   c) C₁₋₃ alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) a halogen,        -   ii) —OH, or        -   iii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl;    -   R⁷ is        -   i) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently        -   i) H,        -   ii) halogen,        -   iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy, or        -   vi) —C(O)N(R¹⁹)₂,        -   wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and            R^(9e) is —C(O)N(R¹⁹)₂;    -   each R¹⁹ is independently        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof,

-   -   one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the        other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein each        C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH and halogen, or    -   R¹ and R² together with the carbon to which they are attached        form a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic        heterocyclyl having 1 or 2 heteroatoms independently selected        from N, O, and S, wherein the C₃₋₇ monocyclic cycloalkyl and the        4-6 membered monocyclic heterocyclyl are each optionally        substituted with one R¹¹ and are each optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy, or    -   R¹ and R² together form ═O.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof,

-   -   one of R¹ and R² is —OH, halogen, or C₁₋₃ alkyl, and the other        of R¹ and R² is halogen or C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together form ═O.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, andthe other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH and halogen. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceuticallyacceptable salt thereof, one of R¹ and R² is H and the other of R¹ andR² is H, halogen, or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH and halogen.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is —CN and the other of R¹ and R² is H,halogen, or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH and halogen. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR¹ and R² is —OH and the other of R¹ and R² is H, halogen, or C₁₋₆alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH and halogen. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, ora pharmaceutically acceptable salt thereof, one of R¹ and R² is halogenand the other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH and halogen. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or apharmaceutically acceptable salt thereof, one of R¹ and R² is C₁₋₆ alkyland the other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein eachC₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH and halogen. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or apharmaceutically acceptable salt thereof, one of R¹ and R² is C₁₋₃ alkyland the other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein theC₁₋₃ alkyl and the C₁₋₆ alkyl are each optionally substituted with 1-3groups independently selected from —OH and halogen. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, orIVc, or a pharmaceutically acceptable salt thereof, one of R¹ and R² isC₁₋₃ alkyl and the other of R¹ and R² is H, halogen, or C₁₋₆ alkyl,wherein the C₁₋₃ alkyl is substituted with 1-3 OH groups. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR¹ and R² is methyl, ethyl, or propyl and the other of R¹ and R² is H,halogen, or C₁₋₆ alkyl, wherein the methyl, ethyl, or propyl are eachsubstituted with one OH group.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is —OH, halogen, or C₁₋₃ alkyl, and the otherof R¹ and R² is halogen or C₁₋₃ alkyl. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, ora pharmaceutically acceptable salt thereof, one of R¹ and R² is —OH andthe other of R¹ and R² is halogen or C₁₋₃ alkyl. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, orIVc, or a pharmaceutically acceptable salt thereof, one of R¹ and R² ishalogen and the other of R¹ and R² is halogen or C₁₋₃ alkyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR¹ and R² is C₁₋₃ alkyl and the other of R¹ and R² is halogen or C₁₋₃alkyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is —OH, fluoro, methyl, or ethyl and the otherof R¹ and R² is fluoro, methyl, or ethyl. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, ora pharmaceutically acceptable salt thereof, one of R¹ and R² is —OH andthe other of R¹ and R² is fluoro, methyl, or ethyl. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, orIVc, or a pharmaceutically acceptable salt thereof, one of R¹ and R² isfluoro and the other of R¹ and R² is fluoro, methyl, or ethyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, one ofR¹ and R² is methyl and the other of R¹ and R² is fluoro, methyl, orethyl. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is ethyl and the other of R¹ and R² is fluoro,methyl, or ethyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² are both fluoro, methyl, or ethyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R¹ andR² are both fluoro. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceuticallyacceptable salt thereof, R¹ and R² are both methyl. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, orIVc, or a pharmaceutically acceptable salt thereof, R¹ and R² are bothethyl. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is —OH and the other of R¹ and R² is methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the C₃₋₇ monocyclic cycloalkyl and the 4-6 memberedmonocyclic heterocyclyl are each optionally substituted with one R¹¹ andare each optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, orIVc, or a pharmaceutically acceptable salt thereof, R¹ and R² togetherwith the carbon to which they are attached form a C₃₋₇ monocycliccycloalkyl optionally substituted with one R¹¹ and optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a C₃₋₇ monocyclic cycloalkylsubstituted with one R¹¹. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceuticallyacceptable salt thereof, R¹ and R² together with the carbon to whichthey are attached form a C₃ cycloalkyl substituted with one R¹¹. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, or IVc, or a pharmaceutically acceptable salt thereof, R¹ andR² together with the carbon to which they are attached form a C₃cycloalkyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with one R¹¹ andoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, ora pharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a 4-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 4-6 membered monocyclic heterocyclyl is substitutedwith one R¹.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform an azetidinyl optionally substituted with one R¹¹ and optionallysubstituted with 1 or 2 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form an azetidinyl substituted withone R¹.

In some embodiments, the compound of Formula I, II, IIa, III, or IV isof Formula V:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa,or IVb is of Formula Va:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, III, or IVa isof Formula Vb:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa,or IVc is of Formula Vc:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a piperidinyl optionally substituted with one R¹¹ and optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a piperidinyl substituted withone R¹.

In some embodiments, the compound of Formula I, II, IIa, III, or IV isof Formula VI:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa,or IVb is of Formula VIa:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, III, or IVa isof Formula VIb:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa,or IVc is of Formula VIc:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a tetrahydropyranyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a tetrahydropyranyl.

In some embodiments, the compound of Formula I, II, IIa, III, or IV isof Formula VII:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa,or IVb is of Formula VIIa:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, III, or IVa isof Formula VIIb:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula I, II, IIa, IIb, III, IIIa,or IVc is of Formula VIIc:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; ii) —S(O)₂C₁₋₆ alkyl;iii) —S(O)₂C₃₋₇ monocyclic cycloalkyl; iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; or v) —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; ii) —S(O)₂C₁₋₃ alkyl;iii) —S(O)₂C₃₋₅ monocyclic cycloalkyl; iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; or v) —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; ii) —S(O)₂C₁₋₃ alkyl;iii) —S(O)₂C₃₋₄ monocyclic cycloalkyl; iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; or v) —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹ is a 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable saltthereof, R¹¹ is a 4 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc,or a pharmaceutically acceptable salt thereof, R¹¹ is oxetanyloptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VIa, VIb, or VIc, or a pharmaceutically acceptable saltthereof, R¹¹ is oxetanyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₁₋₆ alkyl. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₁₋₃ alkyl. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂CH₃.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₃₋₇ monocycliccycloalkyl. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc,or a pharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₃₋₅monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,or VIc, or a pharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₃₋₄monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,or VIc, or a pharmaceutically acceptable salt thereof, R¹¹ is—S(O)₂(cyclopropyl). In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,or VI, or a pharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂CH₃or —S(O)₂(cyclopropyl).

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIc, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R¹¹ is C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, and C₁₋₃ alkoxy. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, or VIc, or a pharmaceutically acceptable salt thereof, R¹¹ is anethyl optionally substituted with 1-3 halogens. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptablesalt thereof, R¹¹ is —CH₂CHF₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹¹ is —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is i) H; ii) C₃₋₇monocyclic or bridged bicyclic cycloalkyl optionally substituted with1-3 groups independently selected from —CN, —OH, halogen, C₁₋₃ alkyl,and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy;iii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from N, O, and S, wherein the 5-6 memberedmonocyclic heteroaryl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy; v) —NH₂; vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy; vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆alkyl can be the same or different and wherein each C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy; viii) C₁₋₆ alkoxy optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl,and C₃₋₇ monocyclic cycloalkyl; or ix) C₁₋₆ alkyl optionally substitutedwith 1-3 groups independently selected from

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy,    -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —CN, —OH, halogen, C₁₋₃        alkyl, and C₁₋₃ alkoxy,    -   f) 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —CN, —OH, halogen,        oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and    -   g) —OC(O)C₁₋₆ alkyl optionally substituted with one —OH.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is i) C₃₋₇ monocyclic orbridged bicyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy; ii) 4-6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iii)C₁₋₆ alkoxy optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl;or iv) C₁₋₆ alkyl optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is C₃₋₇ monocyclic orbridged bicyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is cyclopropyl,cyclobutyl, cyclopentyl, or C₅ bridged bicyclic cycloalkyl, each ofwhich is optionally substituted with 1-3 groups independently selectedfrom —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH and halogen. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,or VIc, or a pharmaceutically acceptable salt thereof, R²¹ iscyclopropyl, cyclobutyl, cyclopentyl, or C₅ bridged bicyclic cycloalkyl,each of which is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, methyl, and —OCH₃. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceuticallyacceptable salt thereof, R²¹ is cyclopropyl optionally substituted withone group selected from —CN, —OH, fluoro, methyl, —CH₂OH, and —OCH₃. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is cyclobutyl optionallysubstituted with one group selected from fluoro, methyl, and —OCH₃. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is cyclopentyl optionallysubstituted with one —OH. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, or VIc, or a pharmaceutically acceptable salt thereof, R²¹ is a C₅bridged bicyclic cycloalkyl optionally substituted with one groupselected from —OH and fluoro. As used herein, a C₅ bridged bicycliccycloalkyl includes but is not limited to:

which is the same as

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is H. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceuticallyacceptable salt thereof, R²¹ is —NH₂. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable saltthereof, R²¹ is —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, and C₁_₃ alkoxy. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, or VIc, or a pharmaceutically acceptable salt thereof, R²¹ is—N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same or differentand wherein each C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is a 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptablesalt thereof, R²¹ is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl,each of which is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is oxetanyl optionallysubstituted with one group selected from methyl, ethyl, and isopropyl.In some embodiments of the compound of Formula I, II, IIa, IIb III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is oxetanyl optionallysubstituted with one methyl. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R²¹is tetrahydrofuranyl optionally substituted with one methyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is tetrahydropyranyloptionally substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is a 5-6 memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromN, O, and S, wherein the 5-6 membered monocyclic heteroaryl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable saltthereof, R²¹ is a 5-membered heteroaryl having 1-4 heteroatomsindependently selected from N, O, and S, wherein the 5-memberedheteroaryl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, methyl, and —OCH₃. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptablesalt thereof, R²¹ is oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, ortriazolyl, each of which is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is oxazolyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is thiazolyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is isoxazolyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is oxadiazolyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is triazolyl optionallysubstituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is a C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceuticallyacceptable salt thereof, R²¹ is a C₁₋₃ alkoxy optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl,and C₃₋₇ monocyclic cycloalkyl. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R²¹is a C₁₋₃ alkoxy. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, orVIc, or a pharmaceutically acceptable salt thereof, R²¹ is —OCH₃.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from: —CN; —OH;halogen; C₁₋₃ alkoxy; C₃₋₇ monocyclic cycloalkyl optionally substitutedwith 1-3 groups independently selected from —CN, —OH, halogen, C₁₋₃alkyl, and C₁₋₃ alkoxy; 4-6 membered monocyclic heterocyclyl having 1 or2 heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy; and —OC(O)C₁₋₆ alkyl optionally substituted with one—OH. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN; —OH;halogen; C₁₋₃ alkoxy; and 4-6 membered monocyclic heterocyclyl having 1or 2 heteroatoms independently selected from N, O, and S, wherein the4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, orVIc, or a pharmaceutically acceptable salt thereof, R²¹ is C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxetanyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable saltthereof, R²¹ is C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, each of which isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxetanyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, or VIc, or a pharmaceutically acceptable saltthereof, R²¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,or tert-butyl, each of which is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl optionallysubstituted with one group selected from —CN, —OH, and oxetanyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl optionallysubstituted with one group selected from —CN and —OH. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is ethyl optionallysubstituted with one group selected from —OH, fluoro, and —OCH₃. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is n-propyl optionallysubstituted with one —OH. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, or VIc, or a pharmaceutically acceptable salt thereof, R²¹ isisopropyl optionally substituted with one group selected from —CN, —OHand —OCH₃. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc,or a pharmaceutically acceptable salt thereof, R²¹ is isobutyloptionally substituted with one —OH. In some embodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, or VIc, or a pharmaceutically acceptable salt thereof, R²¹is tert-butyl optionally substituted with one group selected from —OH,fluoro, and —OCH₃.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl optionallysubstituted with one group selected from —CN, —OH, and oxetanyl; ethyloptionally substituted with one group selected from —OH, fluoro, and—OCH₃; n-propyl optionally substituted with one —OH; isopropyloptionally substituted with one group selected from —CN, —OH and —OCH₃;isobutyl optionally substituted with one —OH; tert-butyl optionallysubstituted with one group selected from —OH, fluoro, and —OCH₃; —OCH₃;cyclopropyl optionally substituted with one group selected from —CN,—OH, fluoro, methyl, —CH₂OH, and —OCH₃; cyclobutyl optionallysubstituted with one group selected from fluoro, methyl, and —OCH₃;cyclopentyl optionally substituted with one —OH; C₅ bridged bicycliccycloalkyl optionally substituted with one group selected from —OH andfluoro; oxetanyl optionally substituted with one group selected frommethyl, ethyl, and isopropyl; tetrahydrofuranyl optionally substitutedwith one methyl; tetrahydropyranyl optionally substituted with onemethyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyloptionally substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl optionallysubstituted with one group selected from —CN and —OH; ethyl optionallysubstituted with one group selected from —OH, fluoro, and —OCH₃;n-propyl optionally substituted with one —OH; isopropyl optionallysubstituted with one group selected from —CN, —OH and —OCH₃; isobutyloptionally substituted with one —OH; tert-butyl optionally substitutedwith one group selected from —OH, fluoro, and —OCH₃; —OCH₃; cyclopropyloptionally substituted with one group selected from —CN, —OH, fluoro,methyl, —CH₂OH, and —OCH₃; cyclobutyl optionally substituted with onegroup selected from fluoro, methyl, and —OCH₃; cyclopentyl optionallysubstituted with one —OH; C₅ bridged bicyclic cycloalkyl optionallysubstituted with one group selected from —OH and fluoro; or oxetanyloptionally substituted with one group selected from methyl, ethyl, andisopropyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl; methylsubstituted with one oxetanyl; —CH₂OH; —CH₂(CN); ethyl; —CH(CH₃)OH;—CH(CH₃)CH₂OH; —CH(CH₃)OCH₃; —CH(OH)CH₂CH₃; isopropyl; —C(CH₃)₂OH;—C(CH₃)₂OCH₃; —C(CH₃)₂CN; tert-butyl; —C(CH₃)₂CH₂OH; —C(CH₃)₂CH₂OCH₃;—C(CH₃)₂CH₂F; —CH(OH)CH(CH₃)₂; —OCH₃; cyclopropyl; cyclopropylsubstituted with one methyl; cyclopropyl substituted with one fluoro;cyclopropyl substituted with one —OCH₃; cyclopropyl substituted with one—OH; cyclopropyl substituted with one —CN; cyclopropyl substituted withone —CH₂OH; cyclobutyl; cyclobutyl substituted with one —OCH₃;cyclobutyl substituted with one methyl; cyclobutyl substituted with onefluoro; cyclopentyl substituted with one —OH; C₅ bridged bicycliccycloalkyl; C₅ bridged bicyclic cycloalkyl substituted with one fluoro;C₅ bridged bicyclic cycloalkyl substituted with one —OH; oxetanyl;oxetanyl substituted with one methyl; oxetanyl substituted with oneethyl; oxetanyl substituted with one isopropyl; tetrahydrofuranyl;tetrahydrofuranyl substituted with one methyl; tetrahydropyranyl;tetrahydropyranyl substituted with one methyl; oxazolyl; thiazolyl;isoxazolyl; oxadiazolyl; or triazolyl substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl; —CH₂OH;—CH₂(CN); ethyl; —CH(CH₃)OH; —CH(CH₃)CH₂OH; —CH(CH₃)OCH₃; —CH(OH)CH₂CH₃;isopropyl; —C(CH₃)₂OH; —C(CH₃)₂OCH₃; —C(CH₃)₂CN; tert-butyl;—C(CH₃)₂CH₂OH; —C(CH₃)₂CH₂OCH₃; —C(CH₃)₂CH₂F; —CH(OH)CH(CH₃)₂; —OCH₃;cyclopropyl; cyclopropyl substituted with one methyl; cyclopropylsubstituted with one fluoro; cyclopropyl substituted with one —OCH₃;cyclopropyl substituted with one —OH; cyclopropyl substituted with one—CN; cyclopropyl substituted with one —CH₂OH; cyclobutyl; cyclobutylsubstituted with one methyl; cyclobutyl substituted with one fluoro;cyclopentyl substituted with one —OH; C₅ bridged bicyclic cycloalkyl; C₅bridged bicyclic cycloalkyl substituted with one fluoro; C₅ bridgedbicyclic cycloalkyl substituted with one —OH; oxetanyl; oxetanylsubstituted with one methyl; oxetanyl substituted with one ethyl; oroxetanyl substituted with one isopropyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl; methylsubstituted with one oxetanyl; ethyl; —CH(CH₃)OH; —CH(CH₃)OCH₃;—CH(OH)CH₂CH₃; isopropyl; —C(CH₃)₂OH; —C(CH₃)₂OCH₃; —C(CH₃)₂CN;tert-butyl; —C(CH₃)₂CH₂OH; —C(CH₃)₂CH₂OCH₃; —C(CH₃)₂CH₂F;—CH(OH)CH(CH₃)₂; —OCH₃; cyclopropyl; cyclopropyl substituted with onemethyl; cyclopropyl substituted with one fluoro; cyclopropyl substitutedwith one —OH; cyclopropyl substituted with one —OCH₃; cyclopropylsubstituted with one —CN; cyclobutyl; cyclobutyl substituted with onemethyl; cyclobutyl substituted with one —OCH₃; cyclobutyl substitutedwith one fluoro; cyclopentyl substituted with one —OH; C₅ bridgedbicyclic cycloalkyl; C₅ bridged bicyclic cycloalkyl substituted with onefluoro; C₅ bridged bicyclic cycloalkyl substituted with one —OH;oxetanyl; oxetanyl substituted with one methyl; oxetanyl substitutedwith one ethyl; oxetanyl substituted with one isopropyl;tetrahydrofuranyl; tetrahydrofuranyl substituted with one methyl;tetrahydropyranyl; tetrahydropyranyl substituted with one methyl;oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl substitutedwith one methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIb, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl; ethyl;—CH(CH₃)OH; isopropyl; —C(CH₃)₂OH; tert-butyl; —OCH₃; cyclopropyl;cyclopropyl substituted with one methyl; cyclopropyl substituted withone —OH; cyclobutyl; cyclobutyl substituted with one methyl; C₅ bridgedbicyclic cycloalkyl; C₅ bridged bicyclic cycloalkyl substituted with onefluoro; C₅ bridged bicyclic cycloalkyl substituted with one —OH;oxetanyl; or oxetanyl substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIb, VIb, or VIc, or apharmaceutically acceptable salt thereof, R²¹ is methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable saltthereof, R¹¹ is:

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H; ii) halogen;iii) C₁₋₆ alkoxy optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl;iv) —NH₂; v) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,and C₁₋₃ alkoxy; vi) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be thesame or different, and wherein each C₁₋₆ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, and C₁₋₃alkoxy; vii) —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the sameor different, and wherein each C₁₋₆ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy;viii) —S(O)₂C₁₋₆ alkyl; ix) —S(O)₂N(R²³)₂, wherein each R²³ isindependently H or C₁₋₆ alkyl; x) C₁₋₆ alkyl optionally substituted with1-3 groups independently selected from

-   -   a) —OH,    -   b) halogen,    -   c) C₁₋₃ alkoxy,    -   d) C₃₋₇ monocyclic cycloalkyl,    -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from oxo and C₁₋₃ alkyl,        and    -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl;        xi) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —OH, halogen, C₁₋₃ alkyl, and        C₁₋₃ alkoxy; xii) 5-6 membered monocyclic heteroaryl having 1-4        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heteroaryl is optionally substituted        with 1-3 groups independently selected from —OH, halogen, C₁₋₃        alkyl, and C₁₋₃ alkoxy; xiii) 4-6 membered monocyclic        heterocyclyl having 1-3 heteroatoms independently selected from        N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is        optionally substituted with 1-3 groups independently selected        from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; xiv)        —COOH; xv) —C(O)N(R¹⁹)₂; or xvi) —C₁₋₃ alkylC(O)N(R¹⁹)₂; wherein        one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is        —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H; ii) ahalogen; iii) C₁₋₆ alkoxy optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇monocyclic cycloalkyl; iv) —NH₂; v) —NH(C₁₋₃ alkyl), wherein the C₁₋₃alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, and C₁₋₃ alkoxy; vi) —N(C₁₋₃ alkyl)₂, wherein eachC₁₋₃ alkyl can be the same or different, and wherein each C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy; vii) C₁₋₆ alkyl optionally substituted with1-3 groups independently selected from —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl; or viii) —C(O)N(R¹⁹)₂; wherein one or moreof R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H; ii) ahalogen; iii) C₁₋₆ alkoxy optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇monocyclic cycloalkyl; iv) C₁₋₆ alkyl optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl; v) C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy; or vi) —C(O)N(R¹⁹)₂; wherein one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H; ii) halogen;iii) —NH₂; iv) —NH(C₁₋₃ alkyl); v) —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃alkyl is the same or different; vi) C₁₋₃ alkyl optionally substitutedwith 1-3 groups independently selected from —OH and halogen; vii) —OCH₃optionally substituted with 1-3 halogen groups; viii) cyclopropyl; orix) —C(O)N(R¹⁹)₂; wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H; ii) halogen;iii) C₁₋₃ alkyl optionally substituted with 1-3 groups independentlyselected from —OH and halogen; iv) —OCH₃ optionally substituted with 1-3halogen groups; v) cyclopropyl; or vi) —C(O)N(R¹⁹)₂; wherein one or moreof R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is H and one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is halogen and one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is fluoro or chloro and one or moreof R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more R⁹ isfluoro and one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,one or more R⁹ is chloro and one or more of R^(9a), R^(9b), R^(9c),R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl and one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —OCH₃ optionallysubstituted with 1-3 fluoro groups and one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —OCH₃ or —OCF₃ and one or more of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —OCH₃ and one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —OCF₃ and one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —NH₂ and one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —NH(C₁₋₆ alkyl),wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy and one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —NH(C₁₋₃ alkyl), whereinthe C₁₋₃ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, and C₁₋₃ alkoxy and one or more of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —NH(C₁₋₃ alkyl) and one or more of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —N(C₁₋₆ alkyl)₂,wherein each C₁₋₆ alkyl can be the same or different, and wherein eachC₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, and C₁₋₃ alkoxy and one or more of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkylcan be the same or different, and wherein each C₁₋₃ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,and C₁₋₃ alkoxy and one or more of R^(9a), R^(9b), R^(9c), R^(9d), andR^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e)is —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkyl is the same or different,and one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —N(CH₃)₂and one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —P(O)(C₁₋₆alkyl)₂, wherein each C₁₋₆ alkyl can be the same or different, andwherein each C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy and one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —P(O)(C₁₋₃ alkyl)₂,wherein each C₁₋₃ alkyl can be the same or different, and wherein eachC₁₋₃ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, and C₁₋₃ alkoxy and one or more of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —P(O)(C₁₋₃ alkyl)₂ and one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —P(O)(CH-3)₂ and one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —S(O)₂C₁₋₆ alkyland one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, oneor more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —S(O)₂N(R²³)₂,wherein each R²³ is independently H or C₁₋₆ alkyl and one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is 5-6 membered monocyclicheteroaryl having 1-4 heteroatoms independently selected from N, O, andS, wherein the 5-6 membered monocyclic heteroaryl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy and one or more of R^(9a), R^(9b), R^(9c),R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is 4-6 membered monocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, andC₁₋₃ alkoxy and one or more of R^(9a), R^(9b), R^(9c), R^(9d), andR^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e)is —COOH and one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e)is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy and one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is cyclopropyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy and one or more of R^(9a), R^(9b), R^(9c),R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is cyclopropyl and one or more of R^(9a), R^(9b), R^(9c),R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from

-   -   a) —OH,    -   b) halogen,    -   c) C₁₋₃ alkoxy,    -   d) C₃₋₇ monocyclic cycloalkyl,    -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from oxo and C₁₋₃ alkyl,        and    -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl; and        wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and        R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl and one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is C₁₋₃ alkyl optionallysubstituted with 1-3 groups independently selected from —OH and halogenand one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is methyloptionally substituted with 1-3 groups independently selected from —OHand fluoro and one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e)is —C(O)N(R¹⁹)₂. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable saltthereof, one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) isethyl optionally substituted with one —OH and one or more of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, V, Va, Vb,Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is methyl, ethyl, —CF₃, —CHF₂, —CH₂OH, or —CH(CH₃)OH and oneor more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof one or moreof R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is or —CH₂OH and one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C₁₋₃alkylC(O)N(R¹⁹)₂ and one or more of R^(9a), R^(9b), R^(9c), R^(9d), andR^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H; ii) fluoro;iii) chloro; iv) methyl optionally substituted with 1-3 groupsindependently selected from —OH and fluoro; v) ethyl optionallysubstituted with one —OH; vi) —OCH₃ optionally substituted with 1-3fluoro groups; vii) cyclopropyl; or viii) —C(O)N(R¹⁹)₂; and wherein oneor more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently H, fluoro, chloro,methyl, ethyl, —OCH₃, —CF₃, —CHF₂, —CH₂OH, —CH(CH₃)OH, —OCF₃,cyclopropyl, —N(CH₃)₂, or —C(O)N(R¹⁹)₂; and wherein one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) are independently H, fluoro, chloro, methyl,ethyl, —OCH₃, —CF₃, —CHF₂, —CH₂OH, —CH(CH₃)OH, —OCF₃, cyclopropyl, or—C(O)N(R¹⁹)₂; and wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are independently H, fluoro, chloro,methyl, ethyl, —CH₂OH, —OCH₃, —CF₃, —OCF₃, cyclopropyl, —N(CH₃)₂, or—C(O)N(R¹⁹)₂; and wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) areindependently H, fluoro, chloro, methyl, ethyl, —CF₃, —OCF₃,cyclopropyl, or —C(O)N(R¹⁹)₂; and wherein one or more of R^(9a), R^(9b),R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb,Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) areindependently H, fluoro, chloro, methyl, ethyl, or —C(O)N(R¹⁹)₂; andwherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one ofR^(9a), R^(9b), R^(9c), and R^(9e) are independently H, fluoro, chloro,methyl, or ethyl. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable saltthereof, R^(9a) is H or fluoro. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, R^(9b) is H or methyl. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, R^(9b) is H, fluoro, ormethyl. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,R^(9c) is H, fluoro, chloro, methyl, ethyl, —CF₃, —OCF₃, or cyclopropyl.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9c) isH, fluoro, and chloro. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable saltthereof, R^(9c) is methyl. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, R^(9e) is H. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, R^(9d) is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁹is independently i) H; ii) —S(O)₂C₁₋₆ alkyl; iii) C₁₋₆ alkyl optionallysubstituted with 1-6 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; iv) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, C₁₋₆ alkyl, and C₁₋₆alkoxy, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy; or v)4-6 membered monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁹is independently i) H; ii) C₁₋₆ alkyl optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl; or iii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-6 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth R¹⁹ is H. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one R¹⁹ is H. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, both R¹⁹ are H.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth R¹⁹ is C₁₋₆ alkyl optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable saltthereof, one or both R¹⁹ is C₁₋₆ alkyl optionally substituted with 1-3groups independently selected from —OH, halogen, and C₁₋₃ alkoxy. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or both R¹⁹ isC₁₋₄ alkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, or Vc, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁹ is C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-6 groups independently selected from —CN,—OH, halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, one or both R¹⁹ is C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-6 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one or both R¹⁹ is C₃₋₅ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth R¹⁹ is —S(O)₂C₁₋₆ alkyl. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, one or both R¹⁹ is 4-6 membered monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from N, O, and S, whereinthe 4-6 membered monocyclic heterocyclyl is optionally substituted with1-6 groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃alkyl, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁹is independently i) H; ii) methyl; iii) ethyl optionally substitutedwith 1 or 2 groups independently selected from —OH, fluoro, and —OCH₃;iv) n-propyl optionally substituted with 1 or 2 groups independentlyselected from fluoro and —OCH₃; v) isopropyl optionally substituted with1 or 2 fluoro groups; vi) n-butyl; vii) isobutyl optionally substitutedwith 1 or 2 fluoro groups; viii) sec-butyl; ix) tert-butyl; x)cyclopropyl optionally substituted with one methyl group, wherein themethyl is optionally substituted with 1-3 groups independently selectedfrom fluoro and —OCH₃; or xi) cyclobutyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁹is independently i) H; ii) methyl; iii) ethyl; iv) —CH₂CH₂OH; v)—CH₂CH₂OCH₃; vi) —CH₂CHF₂; vii) —CH₂C(CH₃)F₂; vii) —CH(CH₃)CH₂F; ix)—CH(CH₂F)₂; x) n-propyl; xi) isopropyl; xii) —CH(CH₃)CHF₂; xiii)—CH₂CH₂CHF₂; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii)—CH₂CH₂CH₂OCH₃; xviii) cyclopropyl; xix) cyclopropyl substituted withone group selected from —CH₂F, —CHF₂ and —CH₂OCH₃; or xx) cyclobutyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁹is independently i) H; ii) methyl; iii) ethyl; iv) —CH₂CH₂OH; v)—CH₂CH₂OCH₃; vi) —CH₂CHF₂; vii) —CH₂C(CH₃)F₂; viii) n-propyl; ix)isopropyl; x) —CH(CH₃)CH₂F; xi) —CH(CH₃)CHF₂; xii) —CH(CH₂F)₂; xiii)—CH₂CH₂CHF₂; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii)cyclopropyl; xviii) cyclopropyl substituted with one group selected from—CH₂F, —CHF₂ and —CH₂OCH₃; or xix) cyclobutyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁹is independently H, methyl, isopropyl, or cyclopropyl, wherein thecyclopropyl is optionally substituted with one group selected from—CH₂F, —CHF₂ and —CH₂OCH₃.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one R¹⁹ isH and the other R¹⁹ is H, methyl, ethyl, or isopropyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R^(9a),R^(9b), R^(9c), and R^(9e) are independently H, fluoro, chloro, methyl,or ethyl and R^(9d) is —C(O)N(R¹⁹)₂; wherein each R^(9d) isindependently H or cyclopropyl, wherein the cyclopropyl is optionallysubstituted with a methyl, and wherein the methyl is optionallysubstituted with 1-3 groups independently selected from fluoro and—OCH₃. In some embodiments, R^(9a), R^(9b), R^(9c), and R^(9e) areindependently H, fluoro, chloro, methyl, or ethyl and R^(9d) is—C(O)N(R¹⁹)₂; wherein each R¹⁹ is independently H or cyclopropyl,wherein the cyclopropyl is optionally substituted with a methyl, andwherein the methyl is optionally substituted with 1-3 groups fluorogroups. In some embodiments, R^(9a), R^(9b), R^(9c), and R^(9e) areindependently H, fluoro, chloro, methyl, or ethyl and R^(9d) is—C(O)NH(R¹⁹); wherein R¹⁹ is cyclopropyl optionally substituted with amethyl, and wherein the methyl is optionally substituted with 1-3 groupsfluoro groups. In some embodiments, R^(9a), R^(9b), R^(9c), and R^(9e)are independently H, fluoro, or chloro and R^(9d) is —C(O)NH(R¹⁹);wherein R¹⁹ is cyclopropyl optionally substituted with a methyl, andwherein the methyl is optionally substituted with 1-3 groups fluorogroups. In some embodiments, R^(9a), R^(9b), and R^(9c) areindependently fluoro or chloro, R^(9e) is H, and R^(9d) is —C(O)NH(R¹⁹);wherein R¹⁹ is cyclopropyl optionally substituted with a methyl, whereinthe methyl is optionally substituted with 1-3 groups fluoro groups. Insome embodiments, R^(9d) is

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R⁷ is i)H; ii) C₁₋₆ alkyl optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl;or iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R⁷ is H.

In some embodiments of the compound of Formula I, II, IIb, IIa, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R⁷ is C₁₋₆alkyl optionally substituted with 1-3 groups independently selected from—OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, R⁷ is methyl,ethyl, isopropyl, or sec-butyl. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, R⁷ is ethyl, isopropyl, or sec-butyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, R⁷ is isopropyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R⁷ is C₃₋₇monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R⁷ iscyclopropyl optionally substituted with one methyl group. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, R⁷ is cyclopropyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R⁷ ismethyl, ethyl, isopropyl, sec-butyl, or cyclopropyl, wherein thecyclopropyl is optionally substituted with one methyl. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IVIVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, R⁷ is ethyl,isopropyl, sec-butyl, or cyclopropyl. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, R⁷ is isopropyl orcyclopropyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isNR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently i) H; ii) C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iii) 4-7 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iv) —C(O)C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, and C₁₋₃ alkoxy; or v) C₁₋₆ alkyloptionally substituted with 1-6 groups independently selected from

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy,    -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —OH, halogen, C₁₋₃ alkyl, and        C₁₋₃ alkoxy, and    -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isNR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently i) H; ii) C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iii) 4-7 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iv) —C(O)C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, and C₁₋₃ alkoxy; or v) C₁₋₆ alkyloptionally substituted with 1-6 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isNR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently i) H; or ii) C₁₋₆ alkyloptionally substituted with 1-6 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is H. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, one of R⁵ and R¹⁶ is H.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is C₃₋₇ monocyclic cycloalkyl optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl,and C₁₋₃ alkoxy. In some embodiments of the compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable saltthereof, one or both of R¹⁵ and R¹⁶ is a cyclobutyl, cyclopentyl, orcyclohexyl, each of which is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is a cyclobutyl optionally substituted with 1 or 2groups independently selected from —OH and fluoro. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or both of R⁵ and R¹⁶ is acyclohexyl optionally substituted with 1 or 2 fluoro groups. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵and R¹⁶ is a cyclobutyl; cyclobutyl substituted with one —OH; cyclobutylsubstituted with 2 fluoro groups; or cyclohexyl substituted with 2fluoro groups.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is 4-7 membered monocyclic heterocyclyl having 1 or2 heteroatoms independently selected from N, O, and S, wherein the 4-7membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, andC₁₋₃ alkoxy. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,one or both of R¹⁵ and R¹⁶ is 5-7 membered monocyclic heterocyclyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or both of R¹⁵ and R¹⁶ istetrahydropyranyl optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵and R¹⁶ is tetrahydropyranyl optionally substituted with one groupselected from fluoro and methyl. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one or both of R¹⁵ and R¹⁶ istetrahydropyranyl; tetrahydropyranyl substituted with one fluoro group;or tetrahydropyranyl substituted with one methyl group.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is a cyclobutyl, cyclopentyl, cyclohexyl, ortetrahydropyranyl, each of which is optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one or both of R¹⁵ and R¹⁶ is —C(O)tert-butyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is C₁₋₆ alkyl optionally substituted with 1-6 groupsindependently selected from

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy,    -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —OH, halogen, C₁₋₃ alkyl, and        C₁₋₃ alkoxy, and    -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one orboth of R¹⁵ and R¹⁶ is C₁₋₆ alkyl optionally substituted with 1-6 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, IIb, III, IIIa, IV,IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵and R¹⁶ is C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and —OCH₃. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or both of R¹⁵ and R¹⁶ isi) methyl; ii) isopropyl; iii) isobutyl optionally substituted with onegroup selected from —OH, fluoro, and —OCH₃; iv) sec-butyl; or v) C₅alkyl optionally substituted with —OCH₃. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one or both of R¹⁵ and R¹⁶ isi) methyl; ii) isopropyl; iii) isobutyl; iv) —CH₂C(CH₃)₂F; v)—CH₂C(CH₃)₂OCH₃; vi) —CH₂C(CH₃)₂OH; vii) sec-butyl; or viii)—CH₂C(CH₃)₂CH₂OCH₃.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R¹⁵ andR¹⁶ are independently i) H; ii) methyl; iii) isopropyl; iv) isobutyloptionally substituted with one group selected from —OH, fluoro, and—OCH₃; v) sec-butyl; vi) C₅ alkyl optionally substituted with —OCH₃;vii) —C(O)(tert-butyl); viii) cyclobutyl optionally substituted with 1or 2 groups independently selected from —OH and fluoro; ix) cyclohexyloptionally substituted with 1 or 2 fluoro groups; or x)tetrahydropyranyl optionally substituted with one group selected fromfluoro and methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R¹⁵ andR¹⁶ are independently i) H; ii) methyl; iii) isopropyl; iv) isobutyl; v)—CH₂C(CH₃)₂F; vi) —CH₂C(CH₃)₂OCH₃; vii) —CH₂C(CH₃)₂OH; viii) sec-butyl;ix) —CH₂C(CH₃)₂CH₂OCH₃; x) —C(O)(tert-butyl); xi) cyclobutyl; xii)cyclobutyl substituted with one —OH; xiii) cyclobutyl substituted with 2fluoro groups; xiv) cyclohexyl substituted with 2 fluoro groups; xv)tetrahydropyranyl; xvi) tetrahydropyranyl substituted with one fluorogroup; or xvii) tetrahydropyranyl substituted with one methyl group. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, R¹⁵ and R¹⁶ areindependently i) H; ii) isopropyl; iii) —CH₂C(CH₃)₂F; iv) —CH₂C(CH₃)₂OH;v) —CH₂C(CH₃)₂OCH₃; vi) —C(O)(tert-butyl); vii) cyclobutyl substitutedwith 2 fluoro groups; viii) cyclohexyl substituted with 2 fluoro groups;or ix) tetrahydropyranyl substituted with one methyl group.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R¹⁵ andR¹⁶ are independently H, methyl, or isobutyl, wherein the isobutyl isoptionally substituted with one group selected from —OH, fluoro, and—OCH₃. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, oneof R¹⁵ and R¹⁶ is H or methyl and the other of R¹⁵ and R¹⁶ is isobutyloptionally substituted with one group selected from —OH, fluoro, and—OCH₃. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, R¹⁵and R¹⁶ are independently H, methyl, isobutyl, —CH₂C(CH₃)₂OCH₃,CH₂C(CH₃)₂OH, or CH₂C(CH₃)₂F.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one of R¹⁵and R¹⁶ is H and the other of R¹⁵ and R¹⁶ is i) isopropyl; iii)—CH₂C(CH₃)₂F; iv) —CH₂C(CH₃)₂OH; v) —CH₂C(CH₃)₂OCH₃; vi)—C(O)(tert-butyl); vii) cyclobutyl substituted with 2 fluoro groups;viii) cyclohexyl substituted with 2 fluoro groups; or ix)tetrahydropyranyl substituted with one methyl group.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is a4-10 membered monocyclic, fused bicyclic, bridged bicyclic, orspirocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic,bridged bicyclic, or spirocyclic heterocyclyl is optionally substitutedwith 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is a 4-8membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl having 1-3 heteroatoms independently selected from N, O,and S, wherein the 4-8 membered monocyclic, fused bicyclic, bridgedbicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-5 R¹⁸. As used herein,

is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, orspirocyclic heterocyclyl with at least one nitrogen ring atom, whereinthe nitrogen ring atom is the point of attachment for the 4-10 memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isazetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl, each of which isoptionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isazetidinyl optionally substituted with 1-4 R¹⁸. In some embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, X is azetidinyl optionallysubstituted with 1-3 R¹⁸. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, X is azetidinyl optionally substituted with 1-2 R¹⁸. Insome embodiments of the compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, or a pharmaceutically acceptable salt thereof, X is pyrrolidinyloptionally substituted with 1-5 R⁸. In some embodiments of the compoundof Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, X is piperidinyl optionally substituted with1-5 R¹⁸. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X ismorpholinyl optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-4 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-3 R¹⁸. In embodiments ofthe compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-3 R¹⁸. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-3 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-4 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is whichis optionally substituted with 1-3 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-4 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-3 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isunsubstituted. In some embodiments of the compound of Formula I, II, Ia,Ib, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X issubstituted with 1-5 R¹⁸. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, X is substituted with 1-4 R¹⁸. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, X is substituted with 1-3 R¹⁸.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X issubstituted with 1-2 R¹⁸

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X issubstituted with one R¹⁸. In some embodiments of the compound of FormulaI, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa,VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptablesalt thereof, X is substituted with two R¹⁸. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, X is substituted with threeR¹⁸. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X issubstituted with four R¹⁸. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, X is substituted with five R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, two R¹⁸are attached to the same carbon.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁸is independently i) —CN; ii) a halogen; iii) —OH; iv) C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; v) C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; vi) —COOH; or vii)—C(O)N(R²²)₂, wherein each R²² is independently H or C₁₋₆ alkyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁸is independently i) a halogen; ii) —OH; or iii) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁸is independently —OH, fluoro, or C₁₋₃ alkyl optionally substituted with1-3 groups independently selected from —OH and halogen.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, each R¹⁸is independently —OH, fluoro, or methyl optionally substituted with 1-3groups independently selected from —OH and fluoro.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two,three, four, or five R¹⁸ is —CN. In some embodiments of the compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceuticallyacceptable salt thereof, one, two, three, four, or five R¹⁸ is ahalogen. In some embodiments of the compound of Formula I, II, IIa, IIb,III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one,two, three, four, or five R¹⁸ is fluoro. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one, two, three, four, or fiveR¹⁸ is —OH. In some embodiments of the compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable salt thereof,one, two, three, four, or five R¹⁸ is —COOH. In some embodiments of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one, two, three, four, or fiveR¹⁸ is —C(O)N(R²²)₂, wherein each R²² is independently H or C₁₋₆ alkyl.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two,three, four, or five R¹⁸ is C₁₋₆ alkoxy optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two,three, four, or five R¹⁸ is C₁₋₆ alkyl optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc, or a pharmaceutically acceptable saltthereof, one, two, three, four, or five R¹⁸ is C₁₋₃ alkyl optionallysubstituted with 1-3 groups independently selected from —OH and halogen.In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two,three, four, or five R¹⁸ is a methyl optionally substituted with 1-3groups independently selected from —OH and fluoro. In some embodimentsof the compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof, one, two, three, four, or fiveR¹⁸ is a methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, one, two,three, four, or five R¹⁸ is fluoro or methyl.

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X isselected from the group consisting of:

In some embodiments of the compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula I, II, IIa, IIb, III, orIIIa, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula I, II, IIa, IIb, III, orIIIa, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula I, II, IIa, IIb, III, orIIIa, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula I, II, IIa, IIb, III, orIIIa, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula I, II, IIa, IIb, III, orIIIa, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula I, II, IIa, IIb, III, orIIIa, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orVI, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orVI, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orVI, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orVI, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orVI, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, the compound is:

or a pharmaceutically acceptable salt thereof.

III. Compositions and Kits

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that comprise one or more of the compoundsprovided herein or pharmaceutically acceptable salts, isomer, or amixture thereof and one or more pharmaceutically acceptable vehiclesselected from carriers, adjuvants and excipients. The compounds providedherein may be the sole active ingredient or one of the activeingredients of the pharmaceutical compositions. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants. Such compositions are prepared in a manner well known in thepharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes,Eds.).

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein (e.g., a compound of Formula I,II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient or carrier. In someembodiments, the pharmaceutical compositions comprise a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for a hepatitis B virus (HBV)infection, human immunodeficiency virus (HIV) infection, cancer, or ahyper-proliferative disease. In some embodiments, the one or moreadditional therapeutic agents include PD1 inhibitors and/or PDL1inhibitors. In some embodiments, the one or more additional therapeuticagents that are therapeutic for HBV infection include PDL1 inhibitorsand/or PDL1 inhibitors. In some embodiments, the one or more additionaltherapeutic agents that are therapeutic for cancer orhyper-proliferative disease include PD1 inhibitors and/or PDL1inhibitors.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for HBV infection. In someembodiments, the one or more additional therapeutic agents is selectedfrom the group consisting of: adefovir (Hepsera®), tenofovir disoproxilfumarate+emtricitabine (Truvada®), tenofovir disoproxil fumarate(Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®),Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-nl (Humoferon®), ribavirin, interferon beta-la(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for HIV infection. In someembodiments, the one or more additional therapeutic agents is selectedfrom the group consisting of: 4′-ethynyl-2-fluoro-2′-deoxyadenosine,bictegravir or a pharmaceutically acceptable salt thereof, abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofoviralafenamide hemifumarate, emtricitabine, and lamivudine, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude PD1 inhibitors and/or PDL1 inhibitors. In some embodiments, theone or more additional therapeutic agents is selected from the groupconsisting of: nivolumab, lambrolizumab, pembrolizumab, pidilizumab,PDR001, TSR-001, atezolizumab, durvalumab, or avelumab, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for cancer or hyper-proliferativedisease. In some embodiments, the one or more additional therapeuticagents is selected from the group consisting of: rituxan, doxorubicin,gemcitabine, pidilizumab, TSR-042, BMS-986016, ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319,GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145,IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117,WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114,IPI-549, INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitril e, and ipilimumab, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical compositions may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In some embodiments, the pharmaceutical compositionsmay be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds provided herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound provided herein orpharmaceutically acceptable salts, isomer, or a mixture thereof, theactive ingredient (such as a compound provided herein) is usuallydiluted by an excipient and/or enclosed within such a carrier that canbe in the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be in the form of a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing, for example,up to 10% by weight of the active compound, soft and hard gelatincapsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combinations thereof. The pharmaceutical compositionscan additionally include lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents; or any combinations thereof.

The pharmaceutical compositions that include at least one compounddescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated so as to provide quick, sustained ordelayed release of the active ingredient (such as a compound providedherein) after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Examples of controlled release systems are given in U.S.Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Anotherformulation for use in the methods of the present disclosure employstransdermal delivery devices (“patches”). Such transdermal patches maybe used to provide continuous or discontinuous infusion of the compoundsprovided herein in controlled amounts. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with materials such as shellac, cetyl alcohol, andcellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. In some embodiments, the compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. In other embodiments, compositions in pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be inhaled directly from the nebulizing device or thenebulizing device may be attached to a facemask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

In one aspect, provided herein are kits that comprise a compoundprovided herein, (e.g., a compound of Formula I, II, IIa, IIb, III,IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa,VIIb, or VIIc), or a pharmaceutically acceptable salt, stereoisomer,prodrug, or solvate thereof, and suitable packaging. In someembodiments, the kit further comprises instructions for use. In someembodiments, the kit comprises a compound provided herein (e.g., acompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or apharmaceutically acceptable salt, stereoisomer, prodrug, or solvatethereof, and a label and/or instructions for use of the compounds in thetreatment of the indications, including the diseases or conditions,described herein.

In some embodiments, the kits further comprise one or more (e.g., one,two, three, four, one or two, one to three, or one to four) additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are articles of manufacture that comprisea compound described herein or pharmaceutically acceptable salts,isomer, or a mixture thereof in a suitable container. In someembodiments, the container may be a vial, jar, ampoule, preloadedsyringe, or intravenous bag.

IV. Methods

The methods provided herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods provided herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the present disclosure maybe used for a variety of purposes, including therapeutic andexperimental purposes. For example, the present disclosure may be usedex vivo to determine the optimal schedule and/or dosing ofadministration of a HPK1 inhibitor for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the present disclosuremay be suited are described below or will become apparent to thoseskilled in the art. The selected compounds may be further characterizedto examine the safety or tolerance dosage in human or non-humansubjects. Such properties may be examined using commonly known methodsto those skilled in the art.

In one aspect, the present disclosure provides methods of inhibitingHPK1 activity in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa,IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treating adisease or disorder associated with increased HPK1 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of increasingT-cell activation in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa,IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treatingcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb,IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma,urothelial cancer. In some embodiments, the cancer is a solid tumor.

In one aspect, the present disclosure provides methods of inhibiting thegrowth or proliferation of cancer cells in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula I, II,IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb,VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition provided herein.

In some embodiments, the above methods further comprise administering atherapeutically effective amount of one or more additional therapeuticagents, or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: Inducible T-cell costimulator(ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blockingantibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47(CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8)agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors,lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors,V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation(VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors,STING agonists, C—X—C chemokine receptor type 4 (CXCR-4) inhibitors,B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusionproteins, MKNK1/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: rituxan, doxorubicin,gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001,atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016,ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319,GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145,IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117,WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114,IPI-549, INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

In one aspect, the present disclosure provides methods of treating orpreventing a hepatitis B virus (HBV) infection in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (e.g., a compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition providedherein.

In some embodiments, the method of treating or preventing a HBVinfection further comprises administering a therapeutically effectiveamount of one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HBV combination drugs, HBVvaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-likereceptor (TLR) modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg)inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton'styrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replicationinhibitors, arginase inhibitors, and other HBV drugs, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1(Humoferon®), ribavirin, interferon beta-la (Avonex®),Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide,Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferonalfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg,Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of entecavir, adefovir, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine and lamivudine, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of tenofovir alafenamide, tenofoviralafenamide fumarate, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In one aspect, the present disclosure provides methods of treating orpreventing a human immunodeficiency virus (HIV) infection in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (e.g., acompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering a therapeutically effectiveamount of one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, tenofovir alafenamide fumarate and tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovirdisoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxilfumarate, or a pharmaceutically acceptable salt of any of the foregoing,or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of emtricitabine and lamivudine, or apharmaceutically acceptable salt of each thereof.

In some embodiments, the one or more additional therapeutic agents isemtricitabine or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovir, tenofovirdisoproxil, tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, tenofovir alafenamide, and tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof, and further comprisesadministering another therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine, or a pharmaceuticallyacceptable salt of each thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof, and further comprises administering anothertherapeutic agent selected from the group consisting of emtricitabineand lamivudine, or a pharmaceutically acceptable salt of each thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovirdisoproxil, tenofovir disoproxil fumarate, and tenofovir disoproxilhemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof, and further comprisesadministering another therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the methods described herein comprise administeringa therapeutically effective amount of a compound provided herein (e.g.,a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or apharmaceutically acceptable salt thereof. In some embodiments, themethods described herein comprise administering a therapeuticallyeffective amount of a pharmaceutical composition provided herein.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in therapy.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofinhibiting hematopoietic progenitor kinase 1 (HPK1) activity in asubject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating a disease or disorder associated with increased hematopoieticprogenitor kinase 1 (HPK1) activity in a subject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofincreasing T-cell activation in a subject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating cancer in a subject in need thereof.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma, andurothelial cancer. In some embodiments, the cancer is a solid tumor.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofinhibiting the growth or proliferation of cancer cells in a subject inneed thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering a therapeutically effective amount of one ormore additional therapeutic agents, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: Inducible T-cell costimulator(ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blockingantibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47(CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8)agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors,lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors,V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation(VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors,STING agonists, C—X—C chemokine receptor type 4 (CXCR-4) inhibitors,B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusionproteins, MKNK1/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: rituxan, doxorubicin,gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001,atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016,ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557,X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443,GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037,AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549,INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitril e, and ipilimumab, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing a hepatitis B virus (HBV) infection in a subjectin need thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering a therapeutically effective amount of one ormore additional therapeutic agents, or a pharmaceutically acceptablethereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of HBV combination drugs, HBVvaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-likereceptor (TLR) modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg)inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucelotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton'styrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replicationinhibitors, arginase inhibitors, and other HBV drugs, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-nl (Humoferon®), ribavirin, interferon beta-la(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of entecavir, adefovir, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine and lamivudine, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of tenofovir alafenamide, tenofoviralafenamide fumarate, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing a human immunodeficiency virus (HIV) infection ina subject in need thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, tenofovir alafenamide fumarate or tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir or a pharmaceuticallyacceptable salt thereof, tenofovir disoproxil, tenofovir disoproxilhemifumarate or tenofovir disoproxil fumarate, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the uses described herein comprise administering atherapeutically effective amount of a compound provided herein (e.g., acompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc), or apharmaceutically acceptable salt thereof.

V. Administration

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with, for example, thecondition of the recipient. An advantage of certain compounds disclosedherein is that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In some embodiments, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The specific dose level of a compound of the present disclosure for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt or pharmaceutically acceptable tautomerthereof, may be between about 1 mg and 4,000 mg, between about 2,000 to4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day,between about 50 to 300 mg/day, between about 75 to 200 mg/day, orbetween about 15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compounds of the present disclosure may be administered to anindividual (e.g., a human) in a therapeutically effective amount. Insome embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful routeand means, such as by oral or parenteral (e.g., intravenous)administration. Therapeutically effective amounts of the compound mayinclude from about 0.00001 mg/kg body weight per day to about 10 mg/kgbody weight per day, such as from about 0.0001 mg/kg body weight per dayto about 10 mg/kg body weight per day, or such as from about 0.001 mg/kgbody weight per day to about 1 mg/kg body weight per day, or such asfrom about 0.01 mg/kg body weight per day to about 1 mg/kg body weightper day, or such as from about 0.05 mg/kg body weight per day to about0.5 mg/kg body weight per day. In some embodiments, a therapeuticallyeffective amount of the compounds provided herein include from about 0.3mg to about 30 mg per day, or from about 30 mg to about 300 mg per day,or from about 0.3 μg to about 30 mg per day, or from about 30 μg toabout 300 μg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 0.1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose, orsuch as from about 0.01 mg per dose to about 1000 mg per dose, or suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose, or such as from about 1 mg per dose toabout 1000 mg per dose. Other therapeutically effective amounts of thecompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc are about 1 mgper dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.Other therapeutically effective amounts of the compound of the presentdisclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675,700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about1000 mg per dose.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundp herein and increasing the dose by increments until clinical efficacyis achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used toincrease the dose. The dosage can be increased daily, every other day,twice per week, once per week, once every two weeks, once every threeweeks, or once a month.

When administered orally, the total daily dosage for a human subject maybe between about 1 mg and 1,000 mg, between about 10-500 mg/day, betweenabout 50-300 mg/day, between about 75-200 mg/day, or between about100-150 mg/day. In some embodiments, the total daily dosage for a humansubject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or1000 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 200, 300, 400, 500,600, 700, or 800 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about300, 400, 500, or 600 mg/day administered in a single dose.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce daily in a method disclosed herein. In some embodiments, a compounddisclosed herein is administered twice daily in a method disclosedherein.

The frequency of dosage of the compound of the present disclosure willbe determined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the HBVinfection, HIV infection, cancer, hyper-proliferative disease, or anyother indication described herein. For example, a compound can beadministered to a human being infected with HBV for a period of from 20days to 180 days or, for example, for a period of from 20 days to 90days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from 1 to 14 days,followed by a period of 7 to 21 days during which the patient does notreceive a dose of the compound, followed by a subsequent period (e.g.,from 1 to 14 days) during which the patient again receives a daily doseof the compound. Alternating periods of administration of the compound,followed by non-administration of the compound, can be repeated asclinically required to treat the patient.

The compounds of the present disclosure or the pharmaceuticalcompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above. Also,administration or treatment with the compounds may be continued for anumber of days; for example, commonly treatment would continue for atleast 7 days, 14 days, or 28 days, for one cycle of treatment. Treatmentcycles are well known in cancer chemotherapy, and are frequentlyalternated with resting periods of about 1 to 28 days, commonly about 7days or about 14 days, between cycles. The treatment cycles, in otherembodiments, may also be continuous.

VI. Combination Therapy

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In some embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two additional therapeutic agents. Insome embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In some embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In some embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In some embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In some embodiments, a compound of the present disclosure isco-administered with one or more additional therapeutic agents.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. The compoundsdisclosed herein may be administered within seconds, minutes, or hoursof the administration of one or more additional therapeutic agents. Forexample, in some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, in other embodiments, a unit dose of one or moreadditional therapeutic agents is administered first, followed byadministration of a unit dose of a compound disclosed herein withinseconds or minutes. In some embodiments, a unit dose of a compounddisclosed herein is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of one ormore additional therapeutic agents. In other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

In some embodiments a compound of Formula I, II, IIa, IIb, III, IIIa,IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, orVIIc, is formulated as a tablet, which may optionally contain one ormore other compounds useful for treating the disease being treated. Incertain embodiments, the tablet can contain another active ingredientfor treating a HBV infection, HIV infection, cancer, or ahyper-proliferative disease. In some embodiments, such tablets aresuitable for once daily dosing

Also provided herein are methods of treatment in which a compound ofFormula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc,VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or a tautomer orpharmaceutically acceptable salt thereof, is given to a patient incombination with one or more additional therapeutic agents or therapy.In some embodiments, the total daily dosage of a compound of Formula I,II, IIa, III, IV, or V, or a tautomer, or a pharmaceutically acceptablesalt thereof, may be about 300 mg/day administered in a single dose fora human subject.

HBV Combination Therapy

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, one tothree, or one to four) additional therapeutic agents. In one embodiment,a method for treating an HBV infection in a human having or at risk ofhaving the infection is provided, comprising administering to the humana therapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three, or one to four) additional therapeuticagents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents which are suitable for treating an HBV infection.

The compounds described herein may be used or combined with one or moreof a chemotherapeutic agent, an immunomodulator, an immunotherapeuticagent, a therapeutic antibody, a therapeutic vaccine, a bispecificantibody and “antibody-like” therapeutic protein (such as DARTs®,Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drugconjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9,zinc finger nucleases, homing endonucleases, synthetic nucleases,TALENs), cell therapies such as CAR-T (chimeric antigen receptorT-cell), and TCR-T (an engineered T cell receptor) agent or anycombination thereof.

In certain embodiments, a compound of Formula (J) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV, such as 3-dioxygenase (IDO)inhibitors, Apolipoprotein A1 modulator, arginase inhibitors, B- andT-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK)inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160inhibitors, CD305 inhibitors, CD4 agonist and modulator, compoundstargeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg),core protein allosteric modulators, covalently closed circular DNA(cccDNA) inhibitors, cyclophilin inhibitors, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, HBsAg inhibitors, HBsAg secretion or assemblyinhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors,HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors,Hepatitis B large envelope protein modulator, Hepatitis B large envelopeprotein stimulator, Hepatitis B structural protein modulator, hepatitisB surface antigen (HBsAg) inhibitors, hepatitis B surface antigen(HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotidereductase, Interleukin-2 ligand, ipi4 inhibitors, lysine demethylaseinhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5inhibitors, killer cell lectin-like receptor subfamily G member 1inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin betareceptor activators, modulators of Axl, modulators of B7-H3, modulatorsof B7-H4, modulators of CD160, modulators of CD161, modulators of CD27,modulators of CD47, modulators of CD70, modulators of GITR, modulatorsof HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A,modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,modulators of TIGIT, modulators of Tim-4, modulators of Tyro,Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, naturalkiller cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoproteininhibitor, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors,Peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K)inhibitors, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, and combinations thereof.

HBV Combination Drugs

Examples of combination drugs for the treatment of HBV include TRUVADA®(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine,and PEG-IFN-alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800(INO-9112 and RG7944).

Other HBV Drugs

Examples of other drugs for the treatment of HBV includealpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides,AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin(gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047,NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551,and ZH-2N, and the compounds disclosed in US20150210682, (Roche), US2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche),WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche),WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche),WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), andUS2015031687A (Roche).

HBV Vaccines

HBV vaccines include both prophylactic and therapeutic vaccines.Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), recombinant hepatitis Bsurface antigen vaccine, Bimmugen, Euforavac, Eutravac,anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP—HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAGvaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hibvaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex,ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay,GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC(NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2,CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500,HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine,HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine(HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,ChronVac-B, TG-1050, and Lm HBV.

HBV DNA Polymerase Inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®),emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovirdipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethylester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate,telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin,lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir,SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxilaspartate, tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidol hydrochloride,ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin,hydroxyurea, mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF), JNJ-440,WF-10,AB-452, ribavirin, IL-12,INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22,CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559,GS-9688, RO-7011785,RG-7854, AB-506, RO-6871765, AIC-649, and IR-103.

Toll-Like Receptor (TLR) Modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim,RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620 (vesatolimod), GSK-2245035,imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197,3M-051, SB-9922, 3M-052, Limtop, D, telratolimod, SP-0509, TMX-30X,TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and the compounds disclosedin US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), andUS20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688 and the compoundsdisclosed in US20140045849 (Janssen), US20140073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),US20080234251 (Array Biopharma), US20080306050 (Array Biopharma),US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics),US20130251673 (Novira Therapeutics), U.S. Pat. No. 9,670,205,US20160289229, U.S. patent application Ser. No. 15/692,161, and U.S.patent application Ser. No. 15/692,093.

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055,IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054,DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, andCYT-003-QbG10.

Examples of TLR7, TLR8 and TLR9 modulators include the compoundsdisclosed in WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen),WO2018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc),WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426(Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661(GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695(Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis),WO2016107536 (Medshine Discovery), WO2018086593 (Livo (Shanghai)Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo DainipponPharma), WO2016023511 (Chia Tai Tianqing Pharmaceutical), WO2017076346(Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149(Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences),WO2018049089 (BristolMyers Squibb), WO2015057655 (Eisai Co Ltd),WO2017001307 (Roche), WO2018005586 (BristolMyers Squibb), WO201704023(3M Co), WO2017163264 (Council of Scientific and Industrial Research(India)), WO2018046460 (GlaxoSmithKline Biologicals), WO2018047081(Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163(Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd), WO2017202704(Roche), WO2018026620 (BristolMyers Squibb), WO2016029077 (JanusBiotherapeutics), WO201803143 (Merck), WO2016096778 (Roche),WO2017190669 (Shanghai De Novo Pharmatech), U.S. Ser. No. 09/884,866(University of Minnesota), WO2017219931 (Sichuan KelunBiotechBiopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054(Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics),WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical),WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University ofKansas), WO2015023958 (University of Kansas).

Interferon Alpha Receptor Ligands

Examples of interferon alpha receptor ligands include interferonalpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®),PEGylated interferon alpha-lb, interferon alpha 1b (HAPGEN®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound interferon), Ypeginterferon alfa-2b(YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®),Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-nl(HUMOFERON®), interferon beta-la (AVONEX®), Shaferon, interferon alfa-2b(Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferonalfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon,Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila),interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), ropeginterferon alfa-2b, rHSA-IFNalpha-2a (recombinant human serum albumin intereferon alpha 2a fusionprotein), rHSA-IFN alpha 2b, recombinant human interferon alpha-(lb, 2a,2b), peginterferon alfa-2b (Amega), peginterferon alfa-2a, Reaferon-EC,Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Instituteof Biological Products), Anterferon, Shanferon, Layfferon, Shang ShengLei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b,SFR-9216, and Interapo (Interapa).

Hyaluronidase Inhibitors

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15,PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165,REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, andREP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4) Inhibitors

Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept,PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cyclophilin Inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030,SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosedin U.S. Pat. No. 8,513,184 (Gilead Sciences), US20140030221 (GileadSciences), US20130344030 (Gilead Sciences), and US20130344029 (GileadSciences).

HBV Viral Entry Inhibitors

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

Examples of antisense oligonucleotide targeting viral mRNA includeISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

Short Interfering RNAs (siRNA) and ddRNAi

Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008,HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

Examples of endonuclease modulators include PGN-514.

Ribonucelotide Reductase Inhibitors

Examples of inhibitors of ribonucleotide reductase include Trimidox.

HBVE Antigen Inhibitors

Examples of HBV E antigen inhibitors include wogonin.

Covalently Closed Circular DNA (cccDNA) Inhibitors

Examples of cccDNA inhibitors include BSBI-25, and CHR-101.

Farnesoid X Receptor Agonist

Examples of farnesoid x receptor agonist such as EYP-001, GS-9674,EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3,NTX-023-1, EP-024297 and GS-8670.

HBV Antibodies

Examples of HBV antibodies targeting the surface antigens of thehepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV HepabulinSN, and fully human monoclonal antibody therapy (hepatitis B virusinfection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal antibodies andpolyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies include HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

Examples of thymosin agonists include Thymalfasin, recombinant thymosinalpha 1 (GeneScience).

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2(IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),IL-15, IL-21, IL-24, and celmoleukin.

Nucleoprotein Modulators

Nucleoprotein modulators may be either HBV core or capsid proteininhibitors. Examples of nucleoprotein modulators include GS-4882,AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109,morphothiadine mesilate, ARB-168786, ARB-880, JNJ-379, RG-7907,HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23.

Examples of capsid inhibitors include the compounds disclosed inUS20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US20140343032 (Roche), WO2014037480 (Roche),US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen),WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen),WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen),WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira),US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira),US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira),US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira), WO2014184350(Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882(Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395(Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881(Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160(Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941(Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen),WO2016168619 (Indiana University), WO2016195982 (The Penn StateFoundation), WO2017001655 (Janssen), WO2017048950 (AssemblyBiosciences), WO2017048954 (Assembly Biosciences), WO2017048962(Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

Examples of transcript inhibitors include the compounds disclosed inWO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche),WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655(Roche), WO2016161268 (Enanta). WO2017001853 (Redex Pharma),WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis),WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma),US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).

Retinoic Acid-Inducible Gene 1 Stimulators

Examples of stimulators of retinoic acid-inducible gene 1 includeSB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198,and ORI-7170, RGT-100.

NOD2 Stimulators

Examples of stimulators of NOD2 include SB-9200.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186,AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib,rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib,IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584,copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093,pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414,SAR-260301,TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2, 3-Dioxygenase (IDO) Pathway Inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat(4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028,GBV-1012, NKTR-218, and the compounds disclosed in US20100015178(Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (FlexusBiosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

PD-1 Inhibitors

Examples of PD-1 inhibitors include cemiplimab, nivolumab,pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001,PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA-170,durvalumab, atezolizumab and mDX-400, JS-001, Camrelizumab, Sintilimab,Sintilimab, tislelizumab, BCD-100, BGB-A333, JNJ-63723283, GLS-010(WBP-3055), CX-072, AGEN-2034, GNS-1480 (Epidermal growth factorreceptor antagonist; Programmed cell death ligand 1 inhibitor), CS-1001,M-7824 (PD-L1/TGF-β bifunctional fusion protein), Genolimzumab,BMS-936559.

PD-L1 Inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224,MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C,TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.

Examples of PD-1 inhibitors include the compounds disclosed inWO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624,WO2014151634 (BristolMyers Squibb Co), WO201317322 (BristolMyers SquibbCo), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp),WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221(Incyte Corp), WO2018118848 (BristolMyers Squibb Co), WO20161266460(BristolMyers Squibb Co), WO2017087678 (BristolMyers Squibb Co),WO2016149351 (BristolMyers Squibb Co), WO2015033299 (Aurigene DiscoveryTechnologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai ResearchInstitute), WO2017066227 (BristolMyers Squibb Co), WO2016142886(Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene DiscoveryTechnologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd;Individual), WO2016142833 (Aurigene Discovery Technologies Ltd),WO2018085750 (BristolMyers Squibb Co), WO2015033303 (Aurigene DiscoveryTechnologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co;Individual; Texas A&M University System), WO2015160641 (BristolMyersSquibb Co), WO2017079669 (Incyte Corp), WO2015033301 (Aurigene DiscoveryTechnologies Ltd), WO2015034820 (BristolMyers Squibb Co), WO2018073754(Aurigene Discovery Technologies Ltd), WO2016077518 (BristolMyers SquibbCo), WO2016057624 (BristolMyers Squibb Co), WO2018044783 (Incyte Corp),WO2016100608 (BristolMyers Squibb Co), WO2016100285 (BristolMyers SquibbCo), WO2016039749 (BristolMyers Squibb Co), WO2015019284 (CambridgeEnterprise Ltd), WO2016142894 (Aurigene Discovery Technologies Ltd),WO2015134605 (BristolMyers Squibb Co), WO2018051255 (Aurigene DiscoveryTechnologies Ltd), WO2018051254 (Aurigene Discovery Technologies Ltd),WO2017222976 (Incyte Corp), WO2017070089 (Incyte Corp), WO2018044963(BristolMyers Squibb Co), WO2013144704 (Aurigene Discovery TechnologiesLtd), WO2018013789 (Incyte Corp), WO2017176608 (BristolMyers Squibb Co),WO2018009505 (BristolMyers Squibb Co), WO2011161699 (Aurigene DiscoveryTechnologies Ltd), WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp),WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317(Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene DiscoveryTechnologies Ltd), WO2015036927 (Aurigene Discovery TechnologiesLtd),WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971(Arising International).

Other examples of PD-1 and/or PDL-1 inhibitors include the compoundsdisclosed in U.S. Provisional Ser. Nos. 62/630,187, 62/640,534,62/736,116, and 62/747,029.

Recombinant Thymosin Alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylatedthymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196),ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062,ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058,RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536,M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015(Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), andUS20130217880 (Ono Pharmaceutical).

KDM Inhibitors

Examples of KDM5 inhibitors include the compounds disclosed inWO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in U.S. Pat.No. 9,186,337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

STING Agonists

Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, andthe compounds disclosed in WO 2018065360 (Biolog Life Science InstituteForschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466(Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (ImmuneSensor), WO 2017106740 (Aduro Biotech), US 20170158724 (GlaxoSmithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO2014179760 (University of California), WO2018098203 (Janssn),WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda),WO2018067423 (Merck), WO2018060323 (Boehringer).

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Examples of NNRTI include the compounds disclosed in WO2018118826(Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108(Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555(Gilead).

HBV Replication Inhibitors

Examples of hepatitis B virus replication inhibitors includeisothiafludine, IQP-HBV, RM-5038, and Xingantie.

Arginase Inhibitors

Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

Gene Therapy and Cell Therapy

Gene therapy and cell therapy includes the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; and genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Gene Editors

Examples of genome editing systems include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system; e.g., cccDNA elimination via targetedcleavage, and altering one or more of the hepatitis B virus (HBV) viralgenes. Altering (e.g., knocking out and/or knocking down) the PreC, C,X, PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminatingPreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interferingwith Precore, Core, X protein, Long surface protein, middle surfaceprotein, S protein (also known as HBs antigen and HBsAg), polymeraseprotein, and/or Hepatitis B spliced protein function (HBe, HBc, HBx,PreS1, PreS2, S, Pol, and/or HBSP) or (3) reducing or eliminating theintracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx,LHBs, MHBs, SHBs, Pol, and/or HBSP proteins. Knockdown of one or more ofthe PreC, C, X, PreSI, PreS2, S, P and/or SP gene(s) is performed bytargeting the gene(s) within HBV cccDNA and/or integrated HBV DNA.

CAR-T Cell Therapy

CAR T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises an HBV antigen-binding domain. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, aCD8+ T cell, or a combination thereof. Cells can be autologous orallogeneic.

TCR-T Cell Therapy

TCR T cell therapy includes T cells expressing HBV-specific T cellreceptors. TCR-T cells are engineered to target HBV derived peptidespresented on the surface of virus-infected cells. In some embodiments,the T-cells express HBV surface antigen (HBsAg)-specific TCR. Examplesof TCR-T therapy directed to treatment of HBV include LTCR-H2-1.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of immunomodulators, TLR modulators, HBsAginhibitors, HBsAg secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors,Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from thegroup consisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, siRNA, miRNA gene therapy agents,sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core orcapsid protein modulators).

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: immunomodulators, TLR modulators,HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus andbispecific antibodies and “antibody-like” therapeutic proteins (such asDARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, siRNA, miRNA gene therapyagents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV coreor capsid protein inhibitors).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with compoundssuch as those disclosed in U.S. Publication No. 2010/0143301 (GileadSciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S.Publication No. 2009/0047249 (Gilead Sciences), U.S. Pat. No. 8,722,054(Gilead Sciences), U.S. Publication No. 2014/0045849 (Janssen), U.S.Publication No. 2014/0073642 (Janssen), WO2014/056953 (Janssen),WO2014/076221 (Janssen), WO2014/128189 (Janssen), U.S. Publication No.2014/0350031 (Janssen), WO2014/023813 (Janssen), U.S. Publication No.2008/0234251 (Array Biopharma), U.S. Publication No. 2008/0306050 (ArrayBiopharma), U.S. Publication No. 2010/0029585 (Ventirx Pharma), U.S.Publication No. 2011/0092485 (Ventirx Pharma), US2011/0118235 (VentirxPharma), U.S. Publication No. 2012/0082658 (Ventirx Pharma), U.S.Publication No. 2012/0219615 (Ventirx Pharma), U.S. Publication No.2014/0066432 (Ventirx Pharma), U.S. Publication No. 2014/0088085(Ventirx Pharma), U.S. Publication No. 2014/0275167 (NoviraTherapeutics), U.S. Publication No. 2013/0251673 (Novira Therapeutics),U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S. Publication No.2014/0030221 (Gilead Sciences), U.S. Publication No. 2013/0344030(Gilead Sciences), U.S. Publication No. 2013/0344029 (Gilead Sciences),US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014/0343032 (Roche), WO2014037480(Roche), U.S. Publication No. 2013/0267517 (Roche), WO2014131847(Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167(Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281(Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888(Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337(Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652(Novira), US20150259324, (Novira), US20150132258 (Novira), U.S. Pat. No.9,181,288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche),US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.),WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (FlexusBiosciences, Inc.), U.S. Publication No. 2014/0330015 (OnoPharmaceutical), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical),U.S. Publication No. 2013/0217880 (Ono pharmaceutical), WO2016057924(Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel), U.S. Pat. No. 9,186,337B2 (OryzonGenomics), and other drugs for treating HBV, and combinations thereof.

HIV Combination Therapy

In certain embodiments, a method for treating or preventing an HIVinfection in a human or animal having or at risk of having the infectionis provided, comprising administering to the human or animal atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HIV infection in a human or animalhaving or at risk of having the infection is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

In certain embodiments, the compounds disclosed herein are formulated asa tablet, which may optionally contain one or more other compoundsuseful for treating HIV. In certain embodiments, the tablet can containanother active ingredient for treating HIV, such as HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, pharmacokinetic enhancers, or anycombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In some embodiments, the additional therapeutic agent may be an anti-HIVagent. In some embodiments, the additional therapeutic agent is selectedfrom the group consisting of HIV combination drugs, HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, immunomodulators, immunotherapeutic agents, antibody-drugconjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zincfinger nucleases, homing nucleases, synthetic nucleases, TALENs), celltherapies (such as chimeric antigen receptor T-cell, CAR-T, andengineered T cell receptors, TCR-T), latency reversing agents, compoundsthat target the HIV capsid (including capsid inhibitors), immune-basedtherapies, phosphatidylinositol 3-kinase (PI3K) inhibitors,alpha-4/beta-7 antagonists, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors,IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators,protein disulfide isomerase inhibitors, complement C5a receptorantagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors,TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinasemodulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicinginhibitors, Rev protein inhibitors, integrin antagonists, nucleoproteininhibitors, splicing factor modulators, COMM domain containing protein 1modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAGprotein inhibitors, HIV POL protein inhibitors, Complement Factor Hmodulators, ubiquitin ligase inhibitors, deoxycytidine kinaseinhibitors, cyclin dependent kinase inhibitors, proprotein convertasePC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reversetranscriptase priming complex inhibitors, G6PD and NADH-oxidaseinhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines,and other HIV therapeutic agents, or any combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, or anycombinations thereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); BIKTARVY® (bictegravir, emtricitabine,tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate,emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; lamivudine and tenofovir disoproxil fumarate;tenofovir and lamivudine; tenofovir alafenamide and emtricitabine;tenofovir alafenamide hemifumarate and emtricitabine; tenofoviralafenamide hemifumarate, emtricitabine, and rilpivirine; tenofoviralafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir;COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®;abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavirand ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine);TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC);atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavirsulfate and ritonavir; darunavir and cobicistat; dolutegravir andrilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir,abacavir sulfate, and lamivudine; lamivudine, nevirapine, andzidovudine; raltegravir and lamivudine; doravirine, lamivudine, andtenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovirdisoproxil; dolutegravir+lamivudine, lamivudine+abacavir+zidovudine,lamivudine+abacavir, lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin;and APH-0812, or any combinations thereof.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine,ACC-007, AIC-292, KM-023, PC-1005, and VM-1500.

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC®(didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine,phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148,MK-8504 and KP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives,integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217,NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173,NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232),anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptideC₂₅P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs.

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176 andGSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, protein kinase C(PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors,ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide,and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitininhibitors such as largazole analogs, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621,AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107; interleukin-15/Fc fusion protein;normferon; peginterferon alfa-2a; peginterferon alfa-2b; recombinantinterleukin-15; RPI-MN; GS-9620; STING modulators; RIG-I modulators;NOD2 modulators; and IR-103.

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed inUS20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953(Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen),US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (ArrayBiopharma), US20080306050 (Array Biopharma), US20100029585 (VentirxPharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma),US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma),US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma),US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Pat. No. 9,670,205 (Gilead Sciences Inc.),US20160289229 (Gilead Sciences Inc.), U.S. patent application Ser. No.15/692,161 (Gilead Sciences Inc.), and U.S. patent application Ser. No.15/692,093 (Gilead Sciences Inc.).

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

Alpha-4/Beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecificantibodies, anti-nef single domain antibodies, anti-Rev antibody,camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIVtherapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab,Immuglo, and MB-66.

Further examples include bavituximab, UB-421, C2F5, 2G12, C4E10,C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121,PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32,7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014 and VRC07.

Additional examples of HIV bispecific antibodies include MGD014.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines, DNA vaccines, CD4-derivedpeptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401),Vacc-4x, Vacc-C5, VAC-3 S, multiclade DNA recombinant adenovirus-5(rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax,Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines,TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4,HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT 123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS 1.HIV-Env,Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001,ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particlevaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusionvaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine,anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cellvaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIVvaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptidevaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVAvaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine,recombinant peptide vaccine (HIV infection), NCI, rgp 160 HIV vaccine,RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIVvaccine, UBI HIV gp120, Vacc-4×+romidepsin, variant gp120 polypeptidevaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI.

Additional HIV Therapeutic Agents

Examples of additional HIV therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

Examples of other drugs for treating HIV include acemannan, alisporivir,BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid,rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy,BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43,HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205,PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452,TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

Gene Therapy and Cell Therapy

Gene therapy and cell therapy include the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; and genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of dendritic cell therapy include AGS-004.

Gene Editors

Examples of gene editing systems include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT101.

CAR-T Cell Therapy

CAR-T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises an HIV antigen-binding domain. The HIV antigens include an HIVenvelope protein or a portion thereof, gp120 or a portion thereof, a CD4binding site on gp120, the CD4-induced binding site on gp120, N glycanon gp120, the V2 of gp120, and the membrane proximal region on gp41. Insome embodiments, the immune effector cell is a T cell or an NK cell. Insome embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or acombination thereof.

Examples of HIV CAR-T cell therapy include VC-CAR-T.

TCR-T Cell Therapy

TCR-T cell therapy includes T cells engineered to target HIV derivedpeptides present on the surface of virus-infected cells.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); BIKTARVY® (bictegravir, emtricitabine,tenofovir alafenamide); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofoviralafenamide hemifumarate, or bictegravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, andbictegravir and a second additional therapeutic agent selected from thegroup consisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, tenofovir alafenamide hemifumarate, andbictegravir and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine.

A compound as disclosed herein may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound(e.g., from 1 mg to 500 mg of compound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30,or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 1 mg to 500 mgof compound) as if each combination of dosages were specifically andindividually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa,IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc)may be combined with the agents provided herein in any dosage amount ofthe compound (e.g., from 1 mg to 500 mg of compound) as if eachcombination of dosages were specifically and individually listed.

Cancer and/or Hyper-Proliferative Disease Combination Therapy

In one embodiment, the compound provided herein may be employed withother therapeutic methods of cancer treatment. Preferably, combinationtherapy with chemotherapeutic, hormonal, antibody, surgical and/orradiation treatments are contemplated.

In some embodiments, the further anti-cancer therapy is surgery and/orradiotherapy. In some embodiments, the further anti-cancer therapy is atleast one additional cancer medicament.

In some embodiments, there is provided a combination comprising acompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof and at least one further cancermedicament.

In some embodiments, there is provided a combination comprising acompound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or apharmaceutically acceptable salt thereof and at least one further cancermedicament, for use in therapy.

In some embodiments, there is provided the use of a combinationcomprising a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa,IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, ora pharmaceutically acceptable salt thereof and at least one cancermedicament, in the manufacture of a medicament for the treatment ofcancer.

Examples of further cancer medicaments include intercalating substancessuch as anthracycline, doxorubicin, idarubicin, epirubicin, anddaunorubicin; topoisomerase inhibitors such as irinotecan, topotecan,camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone,amsacrine, ellipticines and aurintricarboxylic acid; nitrosoureacompounds such as carmustine (BCNU), lomustine (CCNU), and streptozocin;nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine,bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid andifosfamide; alkyl sulfonates such as busulfan and treosulfan; alkylatingagents such as procarbazin, dacarbazin, temozolomid and thiotepa;platinum analogues such as cisplatin, carboplatin, nedaplatin,oxaliplatin, satraplatin, and triplatin tetranitrate; microtubuledisruptive drugs such as vinblastine, colcemid and nocodazole;antifolates like methotrexate, aminopterin, dichloromethotrexat,pemetrexed, raltitrexed and pralatrexate: purine analogues likeazathioprine, mercaptopurine, thioguanine, fludarabine, fludarabinephosphate, pentostatin and cladribine; pyrimidine analogues like5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine;steroids such as gestagene, androgene, glucocorticoids, dexamethasone,prednisolone, and prednisone; anti-cancer antibodies such as monoclonalantibodies, e.g., alemtuzumab, apolizumab, cetuximab, epratuzumab,galiximab, gemtuzumab, ipilimumab, labetuzumab, panitumumab, rituximab,trastuzumab, nimotuzumab, mapatumumab, matuzumab, rhMab ICR62 andpertuzumab, radioactively labeled antibodies and antibody-drugconjugates; anti-cancer peptides such as radioactively labeled peptidesand peptide-drug conjugates; and taxane and taxane analogues such aspaclitaxel and docetaxel.

In certain embodiments, a method for treating or preventing a cancer orhyper-proliferative disease in a human or animal having or at risk ofhaving the cancer or hyper-proliferative disease is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc,V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc as disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, one or two, or one to three) additional therapeutic agents. Inone embodiment, a method for treating a cancer or hyper-proliferativedisease in a human or animal having or at risk of having the cancer orhyper-proliferative disease is provided, comprising administering to thehuman or animal a therapeutically effective amount of a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating a cancer or hyper-proliferative disease, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofone or more additional therapeutic agents which are suitable fortreating cancer or hyper-proliferative disease.

The compounds described herein may be used or combined with one or moreof a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeuticantibody, a bispecific antibody and “antibody-like” therapeutic protein(such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives),an antibody-drug conjugate (ADC), a radiotherapeutic agent, ananti-neoplastic agent, an anti-proliferation agent, an oncolytic virus,a gene modifier or editor (such as CRISPR/Cas9, zinc finger nucleases orsynthetic nucleases, TALENs), a CAR (chimeric antigen receptor) T-cellimmunotherapeutic agent, an engineered T cell receptor (TCR-T), or anycombination thereof. These therapeutic agents may be in the forms ofcompounds, antibodies, polypeptides, or polynucleotides. In oneembodiment, provided herein is a product comprising a compound describedherein and an additional therapeutic agent as a combined preparation forsimultaneous, separate, or sequential use in therapy.

The one or more additional therapeutic agents include, but are notlimited to, an inhibitor, agonist, antagonist, ligand, modulator,stimulator, blocker, activator or suppressor of a gene, ligand,receptor, protein, or factor. Non-limiting examples of additionaltherapeutic agents include:

-   -   Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such        as ABL1), Acetyl-CoA carboxylase (such as ACC1/2), activated CDC        kinase (ACK, such as ACK1), Adenosine deaminase, adenosine        receptor (such as A2B, A2a, A3), Adenylate cyclase, ADP ribosyl        cyclase-1, adrenocorticotropic hormone receptor (ACTH),        Aerolysin, AKT1 gene, Alk-5 protein kinase, Alkaline        phosphatase, Alpha 1 adrenoceptor, Alpha 2 adrenoceptor,        Alpha-ketoglutarate dehydrogenase (KGDH), Aminopeptidase N, AMP        activated protein kinase, anaplastic lymphoma kinase (ALK, such        as ALK1), Androgen receptor, Angiopoietin (such as ligand-1,        ligand-2), Angiotensinogen (AGT) gene, murine thymoma viral        oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2,        AKT3), apolipoprotein A-I (APOA1) gene, Apoptosis inducing        factor, apoptosis protein (such as 1, 2), apoptosis        signal-regulating kinase (ASK, such as ASK1), Arginase (I),        Arginine deiminase, Aromatase, Asteroid homolog 1 (ASTE1) gene,        ataxia telangiectasia and Rad 3 related (ATR) serine/threonine        protein kinase, Aurora protein kinase (such as 1, 2), Axl        tyrosine kinase receptor, Baculoviral IAP repeat containing 5        (BIRC5) gene, Basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2        binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint        cluster region) protein and gene, Beta adrenoceptor,        Beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen        CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte        stimulator ligand, Bone morphogenetic protein-10 ligand, Bone        morphogenetic protein-9 ligand modulator, Brachyury protein,        Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl        tyrosine kinase, Bromodomain and external domain (BET)        bromodomain containing protein (such as BRD2, BRD3, BRD4),        Bruton's tyrosine kinase (BTK), Calmodulin, calmodulin-dependent        protein kinase (CaMK, such as CAMKII), Cancer testis antigen 2,        Cancer testis antigen NY-ESO-1, cancer/testis antigen 1B (CTAG1)        gene, Cannabinoid receptor (such as CB1, CB2), Carbonic        anhydrase, casein kinase (CK, such as CKI, CKII), Caspase (such        as caspase-3, caspase-7, Caspase-9), caspase 8 apoptosis-related        cysteine peptidase CASP8-FADD-like regulator, Caspase        recruitment domain protein-15, Cathepsin G, CCR5 gene,        CDK-activating kinase (CAK), Checkpoint kinase (such as        CHK1,CHK2), chemokine (C—C motif) receptor (such as CCR2, CCR4,        CCR5), chemokine (C—X—C motif) receptor (such as CXCR4, CXCR1        and CXCR2), Chemokine CC21 ligand, Cholecystokinin CCK2        receptor, Chorionic gonadotropin, c-Kit (tyrosine-protein kinase        Kit or CD117), Claudin (such as 6, 18), cluster of        differentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37,        CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44,        CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene,        CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122,        CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276        antigen; clusterin (CLU) gene, Clusterin, c-Met (hepatocyte        growth factor receptor (HGFR)), Complement C3, Connective tissue        growth factor, COP9 signalosome subunit 5, CSF-1        (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4        (cytotoxic T-lymphocyte protein 4) receptor, Cyclin Dl, Cyclin        G1, cyclin-dependent kinases (CDK, such as CDK1, CDK1B, CDK2-9),        cyclooxygenase (such as 1, 2), CYP2B1 gene, Cysteine        palmitoyltransferase porcupine, Cytochrome P450 11B2, Cytochrome        P450 17, cytochrome P450 17A1, Cytochrome P450 2D6, cytochrome        P450 3A4, Cytochrome P450 reductase, cytokine signalling-1,        cytokine signalling-3, Cytoplasmic isocitrate dehydrogenase,        Cytosine deaminase, cytosine DNA methyltransferase, cytotoxic        T-lymphocyte protein-4, DDR2 gene, Delta-like protein ligand        (such as 3, 4), Deoxyribonuclease, Dickkopf-1 ligand,        dihydrofolate reductase (DHFR), Dihydropyrimidine dehydrogenase,        Dipeptidyl peptidase IV, discoidin domain receptor (DDR, such as        DDR1), DNA binding protein (such as HU-beta), DNA dependent        protein kinase, DNA gyrase, DNA methyltransferase, DNA        polymerase (such as alpha), DNA primase, dUTP pyrophosphatase,        L-dopachrome tautomerase, echinoderm microtubule like protein 4,        EGFR tyrosine kinase receptor, Elastase, Elongation factor 1        alpha 2, Elongation factor 2, Endoglin, Endonuclease,        Endoplasmin, Endosialin, Endostatin, endothelin (such as ET-A,        ET-B), Enhancer of zeste homolog 2 (EZH2), Ephrin (EPH) tyrosine        kinase (such as Epha3, Ephb4), Ephrin B2 ligand, epidermal        growth factor, epidermal growth factor receptors (EGFR),        epidermal growth factor receptor (EGFR) gene, Epigen, Epithelial        cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian        erythroblastic leukemia viral oncogene homolog 2) tyrosine        kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4        tyrosine kinase receptor, E-selectin, Estradiol 17 beta        dehydrogenase, Estrogen receptor (such as alpha, beta), Estrogen        related receptor, Eukaryotic translation initiation factor 5A        (EIF5A) gene, Exportin 1, Extracellular signal related kinase        (such as 1, 2), Extracellular signal-regulated kinases (ERK),        Factor (such as Xa, VIIa), farnesoid x receptor (FXR), Fas        ligand, Fatty acid synthase (FASN), Ferritin, FGF-2 ligand,        FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2,        FGF4), Fibronectin, Fms-related tyrosine kinase 3 (Flt3), focal        adhesion kinase (FAK, such as FAK2), folate hydrolase        prostate-specific membrane antigen 1 (FOLH1), Folate receptor        (such as alpha), Folate, Folate transporter 1, FYN tyrosine        kinase, paired basic amino acid cleaving enzyme (FURIN),        Beta-glucuronidase, Galactosyltransferase, Galectin-3,        Ganglioside GD2, Glucocorticoid, glucocorticoid-induced        TNFR-related protein GITR receptor, Glutamate carboxypeptidase        II, glutaminase, Glutathione S-transferase P, glycogen synthase        kinase (GSK, such as 3-beta), Glypican 3 (GPC3),        gonadotropin-releaseing hormone (GNRH), Granulocyte macrophage        colony stimulating factor (GM-CSF) receptor, Granulocyte-colony        stimulating factor (GCSF) ligand, growth factor receptor-bound        protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein)        calcium binding protein, molecular chaperone groEL2 gene, Heat        shock protein (such as 27, 70, 90 alpha, beta), Heat shock        protein gene, Heat stable enterotoxin receptor, Hedgehog        protein, Heparanase, Hepatocyte growth factor, HERV-H LTR        associating protein 2, Hexose kinase, Histamine H2 receptor,        Histone methyltransferase (DOT1L), histone deacetylase (HDAC,        such as 1, 2, 3, 6, 10, 11), Histone H1, Histone H3, HLA class I        antigen (A-2 alpha), HLA class II antigen, Homeobox protein        NANOG, HSPB 1 gene, Human leukocyte antigen (HLA), Human        papillomavirus (such as E6, E7) protein, Hyaluronic acid,        Hyaluronidase, Hypoxia inducible factor-1 alpha (HIF1α),        Imprinted Maternally Expressed Transcript (H19) gene,        mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein        kinase HCK, I-Kappa-B kinase (IKK, such as IKKbe), IL-1 alpha,        IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2        receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7,        IL-8, immunoglobulin (such as G, G1, G2, K, M), Immunoglobulin        Fc receptor, Immunoglobulin gamma Fc receptor (such as I, III,        IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDOl),        indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, insulin        receptor, Insulin-like growth factor (such as 1, 2), Integrin        alpha-4/beta-1, integrin alpha-4/beta-7, Integrin        alpha-5/beta-1, Integrin alpha-V/beta-3, Integrin        alpha-V/beta-5, Integrin alpha-V/beta-6, Intercellular adhesion        molecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta,        gamma), Interferon inducible protein absent in melanoma 2        (AIM2), interferon type I receptor, Interleukin 1 ligand,        Interleukin 13 receptor alpha 2, interleukin 2 ligand,        interleukin-1 receptor-associated kinase 4 (IRAK4),        Interleukin-2, Interleukin-29 ligand, isocitrate dehydrogenase        (such as IDH1, IDH2), Janus kinase (JAK, such as JAK1, JAK2),        Jun N terminal kinase, kallikrein-related peptidase 3 (KLK3)        gene, Killer cell Ig like receptor, Kinase insert domain        receptor (KDR), Kinesin-like protein KIF 11, Kirsten rat sarcoma        viral oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1)        receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral        oncogene homolog (KIT) tyrosine kinase, lactoferrin,        Lanosterol-14 demethylase, LDL receptor related protein-1,        Leukotriene A4 hydrolase, Listeriolysin, L-Selectin, Luteinizing        hormone receptor, Lyase, lymphocyte activation gene 3 protein        (LAG-3), Lymphocyte antigen 75, Lymphocyte function antigen-3        receptor, lymphocyte-specific protein tyrosine kinase (LCK),        Lymphotactin, Lyn (Lck/Yes novel) tyrosine kinase, lysine        demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D),        Lysophosphatidate-1 receptor, lysosomal-associated membrane        protein family (LAMP) gene, Lysyl oxidase homolog 2, lysyl        oxidase protein (LOX), lysyl oxidase-like protein (LOXL, such as        LOXL2), Hematopoietic Progenitor Kinase 1 (HPK1), Hepatocyte        growth factor receptor (MET) gene, macrophage colony-stimulating        factor (MCSF) ligand, Macrophage migration inhibitory fact,        MAGEC1 gene, MAGEC2 gene, Maj or vault protein, MAPK-activated        protein kinase (such as MK2), Mas-related G-protein coupled        receptor, matrix metalloprotease (MMP, such as MMP2, MMP9),        Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4        protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein        Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen        family A3 (MAGEA3) gene, Melanoma associated antigen (such as 1,        2, 3, 6), Membrane copper amine oxidase, Mesothelin, MET        tyrosine kinase, Metabotropic glutamate receptor 1,        Metalloreductase STEAPI (six transmembrane epithelial antigen of        the prostate 1), Metastin, methionine aminopeptidase-2,        Methyltransferase, Mitochondrial 3 ketoacyl CoA thiolase,        mitogen-activate protein kinase (MAPK), mitogen-activated        protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic        target of rapamycin (serine/threonine kinase), mTOR complex        (such as 1, 2), mucin (such as 1, 5A, 16), mut T homolog (MTH,        such as MTH1), Myc proto-oncogene protein, myeloid cell leukemia        1 (MCL1) gene, myristoylated alanine-rich protein kinase C        substrate (MARCKS) protein, NAD ADP ribosyltransferase,        natriuretic peptide receptor C, Neural cell adhesion molecule 1,        Neurokinin 1 (NK1) receptor, Neurokinin receptor, Neuropilin 2,        NF kappa B activating protein, NIMA-related kinase 9 (NEK9),        Nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A B        activating NK receptor, Noradrenaline transporter, Notch (such        as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor),        Nuclear erythroid 2-related factor 2, Nuclear Factor (NF) kappa        B, Nucleolin, Nucleophosmin, nucleophosmin-anaplastic lymphoma        kinase (NPM-ALK), 2 oxoglutarate dehydrogenase,        2,5-oligoadenylate synthetase, O-methylguanine DNA        methyltransferase, Opioid receptor (such as delta), Ornithine        decarboxylase, Orotate phosphoribosyltransferase, orphan nuclear        hormone receptor NR4A1, Osteocalcin, Osteoclast differentiation        factor, Osteopontin, OX-40 (tumor necrosis factor receptor        superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein,        p38 kinase, p38 MAP kinase, p53 tumor suppressor protein,        Parathyroid hormone ligand, peroxisome proliferator-activated        receptors (PPAR, such as alpha, delta, gamma), P-Glycoprotein        (such as 1), phosphatase and tensin homolog (PTEN),        phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase        (PI3K such as alpha, delta, gamma), phosphorylase kinase (PK),        PKN3 gene, placenta growth factor, platelet-derived growth        factor (PDGF, such as alpha, beta), Platelet-derived growth        factor (PDGF, such as alpha, beta), Pleiotropic drug resistance        transporter, Plexin B1, PLK1 gene, polo-like kinase (PLK),        Polo-like kinase 1, Poly ADP ribose polymerase (PARP, such as        PARP1, 2 and 3), Preferentially expressed antigen in melanoma        (PRAME) gene, Prenyl-binding protein (PrPB), Probable        transcription factor PML, Progesterone receptor, Programmed cell        death 1 (PD-1), Programmed cell death ligand 1 inhibitor        (PD-L1), Prosaposin (PSAP) gene, Prostanoid receptor (EP4),        prostate specific antigen, Prostatic acid phosphatase,        proteasome, Protein E7, Protein farnesyltransferase, protein        kinase (PK, such as A, B, C), protein tyrosine kinase, Protein        tyrosine phosphatase beta, Proto-oncogene        serine/threonine-protein kinase (PIM, such as PIM-1, PIM-2,        PIM-3), P-Selectin, Purine nucleoside phosphorylase, purinergic        receptor P2X ligand gated ion channel 7 (P2X7), Pyruvate        dehydrogenase (PDH), Pyruvate dehydrogenase kinase, Pyruvate        kinase (PYK), 5-Alpha-reductase, Raf protein kinase (such as 1,        B), RAF 1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine        kinase receptor, retinoblastoma associated protein, retinoic        acid receptor (such as gamma), Retinoid X receptor, Rheb (Ras        homolog enriched in brain) GTPase, Rho (Ras homolog) associated        protein kinase 2, ribonuclease, Ribonucleotide reductase (such        as M2 subunit), Ribosomal protein S6 kinase, RNA polymerase        (such as I, II), Ron (Recepteur d'Origine Nantais) tyrosine        kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine        kinase)gene, Rosl tyrosine kinase, Runt-related transcription        factor 3, Gamma-secretase, S100 calcium binding protein A9,        Sarco endoplasmic calcium ATPase, Second mitochondria-derived        activator of caspases (SMAC) protein, Secreted frizzled related        protein-2, Semaphorin-4D, Serine protease, serine/threonine        kinase (STK), serine/threonine-protein kinase (TBK, such as        TBK1), signal transduction and transcription (STAT, such as        STAT-1, STAT-3, STAT-5), Signaling lymphocytic activation        molecule (SLAM) family member 7, six-transmembrane epithelial        antigen of the prostate (STEAP) gene, SL cytokine ligand,        smoothened (SMO) receptor, Sodium iodide cotransporter, Sodium        phosphate cotransporter 2B, Somatostatin receptor (such as 1, 2,        3, 4, 5), Sonic hedgehog protein, Son of sevenless (SOS),        Specific protein 1 (Spl) transcription factor, Sphingomyelin        synthase, Sphingosine kinase (such as 1, 2),        Sphingosine-1-phosphate receptor-1, spleen tyrosine kinase        (SYK), SRC gene, Src tyrosine kinase, STAT3 gene, Steroid        sulfatase, Stimulator of interferon genes (STING) receptor,        stimulator of interferon genes protein, Stromal cell-derived        factor 1 ligand, SUMO (small ubiquitin-like modifier),        Superoxide dismutase, Survivin protein, Synapsin 3, Syndecan-1,        Synuclein alpha, T cell surface glycoprotein CD28, tank-binding        kinase (TBK), TATA box-binding protein-associated factor RNA        polymerase I subunit B (TAF1B) gene, T-cell CD3 glycoprotein        zeta chain, T-cell differentiation antigen CD6, T-cell        immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell        surface glycoprotein CD8, Tec protein tyrosine kinase, Tek        tyrosine kinase receptor, telomerase, Telomerase reverse        transcriptase (TERT) gene, Tenascin, TGF beta 2 ligand,        Thrombopoietin receptor, Thymidine kinase, Thymidine        phosphorylase, Thymidylate synthase, Thymosin (such as alpha 1),        Thyroid hormone receptor, Thyroid stimulating hormone receptor,        Tissue factor, TNF related apoptosis inducing ligand, TNFR1        associated death domain protein, TNF-related apoptosis-inducing        ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like        receptor (TLR such as 1-13), topoisomerase (such as I, II, III),        Transcription factor, Transferase, Transferrin, Transforming        growth factor (TGF, such as beta) kinase, Transforming growth        factor TGF-β receptor kinase, Transglutaminase, Translocation        associated protein, Transmembrane glycoprotein NMB, Trop-2        calcium signal transducer, trophoblast glycoprotein (TPBG) gene,        Trophoblast glycoprotein, Tropomyosin receptor kinase (Trk)        receptor (such as TrkA, TrkB, TrkC), Tryptophan 5-hydroxylase,        Tubulin, Tumor necrosis factor (TNF, such as alpha, beta), Tumor        necrosis factor 13C receptor, tumor progression locus 2 (TPL2),        Tumor protein 53 (TP53) gene, Tumor suppressor candidate 2        (TUSC2) gene, Tyrosinase, Tyrosine hydroxylase, tyrosine kinase        (TK), Tyrosine kinase receptor, Tyrosine kinase with        immunoglobulin-like and EGF-like domains (TIE) receptor,        Tyrosine protein kinase ABL1 inhibitor, Ubiquitin, Ubiquitin        carboxyl hydrolase isozyme L5, Ubiquitin thioesterase-14,        Ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), Urease,        Urokinase plasminogen activator, Uteroglobin, Vanilloid VR1,        Vascular cell adhesion protein 1, vascular endothelial growth        factor receptor (VEGFR), V-domain Ig suppressor of T-cell        activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3        receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3 receptor,        Proto-oncogene tyrosine-protein kinase Yes, Wee-1 protein        kinase, Wilms' tumor antigen 1, Wilms' tumor protein, X-linked        inhibitor of apoptosis protein, Zinc finger protein        transcription factor, or any combinations thereof.

Non-limiting examples of additional therapeutic agents may becategorized by their mechanism of action into, for example, thefollowing groups:

-   -   anti-metabolites/anti-cancer agents, such as pyrimidine analogs        floxuridine, capecitabine, cytarabine, CPX-351 (liposomal        cytarabine, daunorubicin), and TAS-118;    -   purine analogs, folate antagonists (such as pralatrexate), and        related inhibitors;    -   antiproliferative/antimitotic agents including natural products,        such as vinca alkaloids (vinblastine, vincristine) and        microtubule disruptors such as taxane (paclitaxel, docetaxel),        vinblastin, nocodazole, epothilones, vinorelbine (NAVELBINE®),        and epipodophyllotoxins (etoposide, teniposide);    -   DNA damaging agents, such as actinomycin, amsacrine, busulfan,        carboplatin, chlorambucil, cisplatin, cyclophosphamide        (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin,        iphosphamide, melphalan, merchlorethamine, mitomycin C,        mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere,        teniposide, etoposide, and triethylenethiophosphoramide;    -   DNA-hypomethylating agents, such as guadecitabine (SGI-110) and        ASTX727;    -   antibiotics such as dactinomycin, daunorubicin, doxorubicin,        idarubicin, anthracyclines, mitoxantrone, bleomycins, and        plicamycin (mithramycin);    -   enzymes such as L-asparaginase which systemically metabolizes        L-asparagine and deprives cells which do not have the capacity        to synthesize their own asparagine;    -   antiplatelet agents;    -   DNAi oligonucleotides targeting Bcl-2, such as PNT2258;    -   agents that activate or reactivate latent human immunodeficiency        virus (HIV), such as panobinostat and romidepsin;    -   asparaginase stimulators, such as crisantaspase (Erwinase®) and        GRASPA (ERY-001, ERY-ASP), and calaspargase pegol;    -   pan-Trk, ROS1 and ALK inhibitors, such as entrectinib and        TPX-0005;    -   anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib        and ceritinib;    -   antiproliferative/antimitotic alkylating agents, such as        nitrogen mustard cyclophosphamide and analogs (melphalan,        chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas        (carmustine) and analogs, streptozocin, and triazenes        (dacarbazine);    -   antiproliferative/antimitotic antimetabolites, such as folic        acid analogs (methotrexate);    -   platinum coordination complexes (cisplatin, oxiloplatinim, and        carboplatin), procarbazine, hydroxyurea, mitotane, and        aminoglutethimide;    -   hormones, hormone analogs (estrogen, tamoxifen, goserelin,        bicalutamide, and nilutamide), and aromatase inhibitors        (letrozole and anastrozole);    -   anticoagulants such as heparin, synthetic heparin salts, and        other inhibitors of thrombin;    -   fibrinolytic agents such as tissue plasminogen activator,        streptokinase, urokinase, aspirin, dipyridamole, ticlopidine,        and clopidogrel;    -   antimigratory agents;    -   antisecretory agents (breveldin);    -   immunosuppressives, such as tacrolimus, sirolimus, azathioprine,        and mycophenolate;    -   growth factor inhibitors, and vascular endothelial growth factor        inhibitors;    -   fibroblast growth factor inhibitors, such as FPA14;    -   anti-VEGFR antibodies, such as IMC-3C5, GNR-011 and tanibirumab;    -   anti-VEGF/DDL4 antibodies, such as ABT-165;    -   anti-cadherins antibodies, such as HKT-288;    -   anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat        containing 15 (LRRC15) antibodies, such as ABBV-085 and        ARGX-110;    -   angiotensin receptor blockers and nitric oxide donors;    -   antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx,        EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), and        IONIS-STAT3-2.5Rx;    -   DNA interference oligonucleotides, such as PNT2258 and AZD-9150;    -   anti-ANG-2 antibodies, such as MEDI3617, and LY3127804;    -   anti-ANG-1/ANG-2 antibodies, such as AMG-780;    -   anti-MET/EGFR antibodies, such as LY3164530;    -   anti-EGFR antibodies, such as ABT-414, AMG-595, necitumumab,        ABBV-221, depatuxizumab mafodotin (ABT-414), tomuzotuximab,        ABT-806, vectibix, modotuximab, and RM-1929;    -   anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820,        and FPA-008 (cabiralizumab);    -   anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, and        ABBV-428;    -   anti-endoglin antibodies, such as TRC105 (carotuximab);    -   anti-CD45 antibodies, such as 131I-BC8 (lomab-B);    -   anti-HER3 antibodies, such as LJM716, and GSK2849330;    -   anti-HER2 antibodies, such as margetuximab, MEDI4276, and        BAT-8001;    -   anti-HLA-DR antibodies, such as IMMU-114;    -   anti-IL-3 antibodies, such as JNJ-56022473;    -   anti-OX40 antibodies, such as MEDI6469, MEDI6383, MEDI0562        (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998,        INCAGN1949, BMS-986178, GBR-8383, and ABBV-368;    -   anti-EphA3 antibodies, such as KB-004;    -   anti-CD20 antibodies, such as obinutuzumab, IGN-002;    -   anti-CD20/CD3 antibodies, such as RG7828;    -   anti-CD37 antibodies, such as AGS67E, and otlertuzumab        (TRU-016);    -   anti-ENPP3 antibodies, such as AGS-16C3F;    -   anti-FGFR-3 antibodies, such as LY3076226, and B-701;    -   anti-FGFR-2 antibodies, such as GAL-F2;    -   anti-C5 antibodies, such as ALXN-1210;    -   anti-CD27 antibodies, such as varlilumab (CDX-1127);    -   anti-TROP-2 antibodies, such as IMMU-132    -   anti-NKG2a antibodies, such as monalizumab;    -   anti-VISTA antibodies, such as HMBD-002;    -   anti-PVRIG antibodies, such as COM-701;    -   anti-EpCAM antibodies, such as VB4-845;    -   anti-BCMA antibodies, such as GSK-2857916;    -   anti-CEA antibodies, such as RG-7813;    -   anti-cluster of differentiation 3 (CD3) antibodies, such as        MGD015;    -   anti-folate receptor alpha antibodies, such as IMGN853;    -   MCL-1 inhibitors, such as AMG-176, S-64315, AZD-5991, 483-LM,        A-1210477, UMI-77, and JKY-5-037;    -   epha2 inhibitors, such as MM-310;    -   anti LAG-3 antibodies, such as relatlimab (ONO-4482), LAG-525,        MK-4280, and REGN-3767;    -   raf kinase/VEGFR inhibitors, such as RAF-265;    -   polycomb protein (EED) inhibitors, such as MAK683;    -   anti-fibroblast activation protein (FAP)/IL-2R antibodies, such        as RG7461;    -   anti-fibroblast activation protein (FAP)/TRAIL-R2 antibodies,        such as RG7386;    -   anti-fucosyl-GM1 antibodies, such as BMS-986012;    -   p38 MAP kinase inhibitors, such as ralimetinib;    -   PRMT1 inhibitors, such as MS203;    -   Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;    -   FLT3-ITD inhibitors, such as BCI-332;    -   Nuclear erythroid 2-related factor 2 stimulators, such as        omaveloxolone (RTA-408);    -   Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195,        and ONO-7579;    -   anti-ICOS antibodies, such as JTX-2011, and GSK3359609;    -   anti-DR5 (TRAIL2) antibodies, such as DS-8273;    -   anti-GD2 antibodies, such as APN-301;    -   anti-interleukin-17 (IL-17) antibodies, such as CJM-112;    -   anti-carbonic anhydrase IX antibodies, such as TX-250;    -   anti-CD38-attenukine, such as TAK573;    -   anti-Mucin 1 antibodies, such as gatipotuzumab;    -   Mucin 1 inhibitors, such as GO-203-2C;    -   MARCKS protein inhibitors, such as BIO-11006;    -   Folate antagonists, such as arfolitixorin;    -   Galectin-3 inhibitors, such as GR-MD-02;    -   Phosphorylated P68 inhibitors, such as RX-5902;    -   CD95/TNF modulators, such as ofranergene obadenovec;    -   PI3K/Akt/mTOR inhibitors, such as ABTL-0812;    -   pan-PIM kinase inhibitors, such as INCB-053914;    -   IL-12 gene stimulators, such as EGEN-001, and tavokinogene        telseplasmid;    -   Heat shock protein HSP90 inhibitors, such as TAS-116, and        PEN-866;    -   VEGF/HGF antagonists, such as MP-0250;    -   SYK tyrosine kinase/FLT3 tyrosine kinase inhibitors, such as        TAK-659;    -   SYK tyrosine kinase/JAK tyrosine kinase inhibitors, such as        ASN-002;    -   FLT3 tyrosine kinase inhibitor, such as FF-10101;    -   FLT3 tyrosine kinase agonist, such as CDX-301;    -   FLT3/MEK1 inhibitors, such as E-6201;    -   IL-24 antagonist, such as AD-IL24;    -   RIG-I agonists, such as RGT-100;    -   Aerolysin stimulators, such as topsalysin;    -   P-Glycoprotein 1 inhibitors, such as HM-30181A;    -   CSF-1 antagonists, such as ARRY-382, and BLZ-945;    -   anti-Mesothelin antibodies, such as SEL-403;    -   Thymidine kinase stimulators, such as aglatimagene besadenovec;    -   Polo-like kinase 1 inhibitors, such as PCM-075;    -   TLR-7 agonists, such as TMX-101 (imiquimod);    -   NEDD8 inhibitors, such as pevonedistat (MLN-4924), and TAS-4464;    -   Pleiotropic pathway modulators, such as avadomide (CC-122);    -   FoxM1 inhibitors, such as thiostrepton;    -   Anti-MUC1 antibodies, such as Mab-AR-20.5;    -   anti-CD38 antibodies, such as isatuximab, and MOR-202;    -   UBA1 inhibitors, such as TAK-243;    -   Src tyrosine kinase inhibitors, such as VAL-201;    -   VDAC/HK inhibitors, such as VDA-1102;    -   BRAF/PI3K inhibitors, such as ASN-003;    -   Elf4a inhibitors, such as rohinitib, eFT226;    -   TP53 gene stimulators, such as ad-p53;    -   PD-L1/EGFR inhibitors, such as GNS-1480;    -   Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;    -   SIRT3 inhibitors, such as YC8-02;    -   Stromal cell-derived factor 1 ligand inhibitors, such as        olaptesed pegol (NOX-A12);    -   IL-4 receptor modulators, such as MDNA-55;    -   Arginase-I stimulators, such as pegzilarginase;    -   Topoisomerase I inhibitor/hypoxia inducible factor-1 alpha        inhibitors, such as PEG-SN38 (firtecan pegol);    -   Hypoxia inducible factor-1 alpha inhibitors, such as PT-2977,        and PT-2385;    -   CD122 agonists such as NKTR-214;    -   p53 tumor suppressor protein stimulators such as kevetrin;    -   Mdm4/Mdm2 p53-binding protein inhibitors, such as ALRN-6924;    -   kinesin spindle protein (KSP) inhibitors, such as filanesib        (ARRY-520);    -   CD80-fc fusion protein inhibitors, such as FPT-155;    -   Menin and mixed lineage leukemia (MLL) inhibitors such as        KO-539;    -   Liver x receptor agonists, such as RGX-104;    -   IL-10 agonists, such as AM-0010;    -   EGFR/ErbB-2 inhibitors, such as varlitinib;    -   VEGFR/PDGFR inhibitors, such as vorolanib;    -   IRAK4 inhibitors, such as CA-4948;    -   anti-TLR-2 antibodies, such as OPN-305;    -   Calmodulin modulators, such as CBP-501;    -   Glucocorticoid receptor antagonists, such as relacorilant        (CORT-125134);    -   Second mitochondria-derived activator of caspases (SMAC) protein        inhibitors, such as BI-891065;    -   Lactoferrin modulators, such as LTX-315;    -   Kit tyrosine kinase/PDGF receptor alpha antagonists such as        DCC-2618;    -   KIT inhibitors, such as PLX-9486;    -   Exportin 1 inhibitors, such as eltanexor;    -   EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;    -   anti-CD33 antibodies, such as IMGN-779;    -   anti-KMA antibodies, such as MDX-1097;    -   anti-TIM-3 antibodies, such as TSR-022, LY-3321367, and MBG-453;    -   anti-CD55 antibodies, such as PAT-SC1;    -   anti-PSMA antibodies, such as ATL-101;    -   anti-CD100 antibodies, such as VX-15;    -   anti-EPHA3 antibodies, such as fibatuzumab;    -   anti-Erbb antibodies, such as CDX-3379, HLX-02, and        seribantumab;    -   anti-APRIL antibodies, such as BION-1301;    -   Anti-Tigit antidbodies, such as BMS-986207, and RG-6058;    -   CHST15 gene inhibitors, such as STNM-01;    -   RAS inhibitors, such as NEO-100;    -   Somatostatin receptor antagonist, such as OPS-201;    -   CEBPA gene stimulators, such as MTL-501;    -   DKK3 gene modulators, such as MTG-201;    -   p70s6k inhibitors, such as MSC2363318A;    -   methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891,        and APL-1202;    -   arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;    -   anti-programmed cell death protein 1 (anti-PD-1) antibodies,        such as nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab        (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab, CAS Reg. No.        1374853-91-4), pidilizumab, PF-06801591, BGB-A317, GLS-010        (WBP-3055), AK-103 (HX-008), MGA-012, BI-754091, REGN-2810        (cemiplimab), AGEN-2034, JS-001, JNJ-63723283, genolimzumab        (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306, and        anti-programmed death-ligand 1 (anti-PD-L1) antibodies such as        BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736),        avelumab, CK-301, (MSB0010718C), MEDI0680, CX-072, CBT-502,        PDR-001 (spartalizumab), TSR-042 (dostarlimab), JTX-4014,        BGB-A333, SHR-1316, CS-1001 (WBP-3155), KN-035, IBI-308,        FAZ-053, and MDX1105-01;    -   PD-L1/VISTA antagonists such as CA-170;    -   anti-PD-L1/TGFβ antibodies, such as M7824;    -   anti-transferrin antibodies, such as CX-2029;    -   anti-IL-8 (Interleukin-8) antibodies, such as HuMax-Inflam;    -   ATM (ataxia telangiectasia) inhibitors, such as AZD0156;    -   CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib),        SRA737, and RG7741 (CHK1/2);    -   CXCR4 antagonists, such as BL-8040, LY2510924, burixafor        (TG-0054), X4P-002, and X4P-001-IO;    -   EXH2 inhibitors, such as GSK2816126;    -   HER2 inhibitors, such as neratinib, and tucatinib (ONT-380);    -   KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, and        GSK-2879552;    -   CXCR2 antagonists, such as AZD-5069;    -   GM-CSF antibodies, such as lenzilumab;    -   DNA dependent protein kinase inhibitors, such as MSC2490484A        (nedisertib), VX-984, and AsiDNA (DT-01);    -   protein kinase C (PKC) inhibitors, such as LXS-196, and        sotrastaurin;    -   Selective estrogen receptor downregulators (SERD), such as        fulvestrant (Faslodex®), RG6046, RG6047, elacestrant (RAD-1901)        and AZD9496;    -   Selective estrogen receptor covalent antagonists (SERCAs), such        as H3B-6545;    -   selective androgen receptor modulator (SARM), such as GTX-024,        and darolutamide;    -   transforming growth factor-beta (TGF-beta) kinase antagonists,        such as galunisertib;    -   anti-transforming growth factor-beta (TGF-beta) antibodies, such        as LY3022859, NIS793, and XOMA 089;    -   bispecific antibodies, such as MM-141 (IGF-1/ErbB3), MM-111        (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD-137/HER2),        AFM26 (BCMA/CD16A), JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3),        RG7802 (CEA/CD3), ERY-974 (CD3/GPC3) vancizumab        (angiopoietins/VEGF), PF-06671008 (Cadherins/CD3), AFM-13        (CD16/CD30), APV0436 (CD123/CD3), flotetuzumab (CD123/CD3),        REGN-1979 (CD20/CD3), MCLA-117 (CD3/CLEC12A), MCLA-128        (HER2/HER3), JNJ-0819, JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3),        MGD-013 (PD-1/LAG-3), AK-104 (CTLA-4/PD-1), AMG-330 (CD33/CD3),        AMG-420 (BCMA/CD3), BI-836880 (VEFG/ANG2), JNJ-63709178        (CD123/CD3), MGD-007 (CD3/gpA33), and MGD-009 (CD3/B7H3);    -   Mutant selective EGFR inhibitors, such as PF-06747775, EGF816        (nazartinib), ASP8273, ACEA-0010, and BI-1482694;    -   Anti-GITR (glucocorticoid-induced tumor necrosis factor        receptor-related protein) antibodies, such as MEDI1873, FPA-154,        INCAGN-1876, TRX-518, BMS-986156, MK-1248, and GWN-323;    -   anti-delta-like protein ligand 3 (DDL3) antibodies, such as        rovalpituzumab tesirine;    -   anti-clusterin antibodies, such as AB-16B5;    -   anti-Ephrin-A4 (EFNA4) antibodies, such as PF-06647263;    -   anti-RANKL antibodies, such as denosumab;    -   anti-mesothelin antibodies, such as BMS-986148, and        Anti-MSLN-MMAE;    -   anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such        as lifastuzumab;    -   anti-c-Met antibodies, such as ABBV-399;    -   Adenosine A2A receptor antagonists, such as CPI-444, AZD-4635,        preladenant, and PBF-509;    -   Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as        CPI-613;    -   XPO1 inhibitors, such as selinexor (KPT-330);    -   Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib        (AG-221);    -   IDH1 inhibitors such as AG-120, and AG-881 (IDH1 and IDH2),        IDH-305, and BAY-1436032;    -   interleukin-3 receptor (IL-3R) modulators, such as SL-401;    -   Arginine deiminase stimulators, such as pegargiminase        (ADI-PEG-20);    -   antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylyl        cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla),        milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin,        DCDT2980S, polatuzumab vedotin, SGN-CD70A, SGN-CD19A, inotuzumab        ozogamicin, lorvotuzumab mertansine, SAR3419, isactuzumab        govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201        (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402,        177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab        ravtansine, CX-2009, SAR-566658, W-0101, polatuzumab vedotin,        and ABBV-085;    -   claudin-18 inhibitors, such as claudiximab;    -   β-catenin inhibitors, such as CWP-291;    -   anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006,        IPH-53, and BMS-986179;    -   CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, and        PSB-12425;    -   CD39/CD73 antagonists, such as PBF-1662;    -   chemokine receptor 2 (CCR) inhibitors, such as PF-04136309,        CCX-872, and BMS-813160 (CCR2/CCR5);    -   thymidylate synthase inhibitors, such as ONX-0801;    -   ALK/ROS1 inhibitors, such as lorlatinib;    -   tankyrase inhibitors, such as G007-LK;    -   Mdm2 p53-binding protein inhibitors, such as CMG-097, and        HDM-201;    -   c-PIM inhibitors, such as PIM447;    -   BRAF inhibitors, such as dabrafenib, vemurafenib, encorafenib        (LGX818), and PLX8394;    -   sphingosine kinase-2 (SK2) inhibitors, such as Yeliva®        (ABC294640);    -   cell cycle inhibitors, such as selumetinib (MEK1/2), and        sapacitabine;    -   AKT inhibitors such as MK-2206, ipatasertib, afuresertib,        AZD5363, ARQ-092, capivasertib, and triciribine;    -   anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such        as tremelimumab, AGEN-1884, and BMS-986218;    -   c-MET inhibitors, such as AMG-337, savolitinib, tivantinib        (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208,        JNJ-38877618 (OMO-1), merestinib, and HQP-8361;    -   c-Met/VEGFR inhibitors, such as BMS-817378, and TAS-115;    -   c-Met/RON inhibitors, such as BMS-777607;    -   BRAF/EGFR inhibitors, such as BGB-283;    -   bcr/abl inhibitors, such as rebastinib, and asciminib;    -   MNK1/MNK2 inhibitors, such as eFT-508;    -   mTOR inhibitor/cytochrome P450 3A4 stimulators, such as TYME-88    -   lysine-specific demethylase-1 (LSD1) inhibitors, such as        CC-90011;    -   Pan-RAF inhibitors, such as LY3009120, LXH254, and TAK-580;    -   Raf/MEK inhibitors, such as RG7304;    -   CSF1R/KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);    -   kinase inhibitors, such as vandetanib;    -   E selectin antagonists, such as GMI-1271;    -   differentiation inducers, such as tretinoin;    -   epidermal growth factor receptor (EGFR) inhibitors, such as        osimertinib (AZD-9291);    -   topoisomerase inhibitors, such as doxorubicin, daunorubicin,        dactinomycin, eniposide, epirubicin, etoposide, idarubicin,        irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan,        irinotecan, MM-398 (liposomal irinotecan), vosaroxin and        GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib        (ACEA-0010), and irofulven (MGI-114);    -   corticosteroids, such as cortisone, dexamethasone,        hydrocortisone, methylprednisolone, prednisone, and        prednisolone;    -   growth factor signal transduction kinase inhibitors;    -   nucleoside analogs, such as DFP-10917;    -   Axl inhibitors, such as BGB-324 (bemcentinib), and SLC-0211;    -   BET inhibitors, such as INCB-054329, INCB057643, TEN-010,        AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib),        NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260,        ZEN3694, FT-1101, RG-6146, CC-90010, mivebresib, BI-894999,        PLX-2853, PLX-51107, CPI-0610, and GS-5829;    -   PARP inhibitors, such as olaparib, rucaparib, veliparib,        talazoparib, ABT-767, and BGB-290;    -   Proteasome inhibitors, such as ixazomib, carfilzomib        (Kyprolis®), and marizomi;    -   Glutaminase inhibitors, such as CB-839;    -   Vaccines, such as peptide vaccine TG-01 (RAS), GALE-301,        GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410,        VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S,        SVN53-67/M57-KLH, IMU-131; bacterial vector vaccines such as        CRS-207/GVAX, axalimogene filolisbac (ADXS11-001); adenovirus        vector vaccines such as nadofaragene firadenovec; autologous        Gp96 vaccine; dendritic cells vaccines, such as CVactm,        stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM,        rocapuldencel-T (AGS-003), DCVAC, CVac™, stapuldencel-T,        eltrapuldencel-T, SL-701, BSK01™, ADXS31-142; oncolytic vaccines        such as, talimogene laherparepvec, pexastimogene devacirepvec,        GL-ONC1, MG1-MA3, parvovirus H-I, ProstAtak, enadenotucirev,        MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as        CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax™;        tumor cell vaccines, such as Vigil® (IND-14205), Oncoquest-L        vaccine; live attenuated, recombinant, serotype 1 poliovirus        vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457;        DPV-001 a tumor-derived, autophagosome enriched cancer vaccine;        RNA vaccines such as CV-9209, LV-305; DNA vaccines, such as        MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara        vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax™;        GI-6301; GI-6207; and GI-4000;    -   anti-DLL4 (delta like ligand 4) antibodies, such as demcizumab;    -   STAT-3 inhibitors, such as napabucasin (BBI-608);    -   ATPase p97 inhibitors, such as CB-5083;    -   smoothened (SMO) receptor inhibitors, such as Odomzo®        (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449),        BMS-833923, glasdegib (PF-04449913), LY2940680, and        itraconazole;    -   interferon alpha ligand modulators, such as interferon alpha-2b,        interferon alpha-2a biosimilar (Biogenomics), ropeginterferon        alfa-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon        (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon,        Ro-25-3036), interferon alfa-2a follow-on biologic        (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on        biologic (Biosidus—Bioferon, Citopheron, Ganapar, Beijing Kawin        Technology—Kaferon), Alfaferone, pegylated interferon alpha-lb,        peginterferon alfa-2b follow-on biologic (Amega), recombinant        human interferon alpha-lb, recombinant human interferon        alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN        alpha 2b conjugate, Dynavax (SD-101), and interferon alfa-nl        (Humoferon, SM-10500, Sumiferon);    -   interferon gamma ligand modulators, such as interferon gamma        (OH-6000, Ogamma 100);    -   IL-6 receptor modulators, such as tocilizumab, siltuximab, and        AS-101 (CB-06-02, IVX-Q-101);    -   Telomerase modulators, such as, tertomotide (GV-1001, HR-2802,        Riavax) and imetelstat (GRN-163, JNJ-63935937);    -   DNA methyltransferases inhibitors, such as temozolomide        (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110),        KRX-0402, RX-3117, RRx-001, and azacitidine;    -   DNA gyrase inhibitors, such as pixantrone and sobuzoxane;    -   Bcl-2 family protein inhibitors, such as ABT-263, venetoclax        (ABT-199), ABT-737, and AT-101;    -   Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab        (anti-Notch2/3), and BMS-906024;    -   anti-myostatin inhibitors, such as landogrozumab;    -   hyaluronidase stimulators, such as PEGPH-20;    -   Wnt pathway inhibitors, such as SM-04755, PRI-724, and WNT-974;    -   gamma-secretase inhibitors, such as PF-03084014, MK-0752, and        RO-4929097;    -   Grb-2 (growth factor receptor bound protein-2) inhibitors, such        as BP1001;    -   TRAIL pathway-inducing compounds, such as ONC201, and ABBV-621;    -   Focal adhesion kinase inhibitors, such as VS-4718, defactinib,        and GSK2256098;    -   hedgehog inhibitors, such as saridegib, sonidegib (LDE225),        glasdegib and vismodegib;    -   Aurora kinase inhibitors, such as alisertib (MLN-8237), and        AZD-2811, AMG-900, barasertib, and ENMD-2076;    -   HSPB 1 modulators (heat shock protein 27, HSP27), such as        brivudine, and apatorsen;    -   ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803,        VX-970 (berzosertib) and VX-970;    -   mTOR inhibitors, such as sapanisertib and vistusertib (AZD2014),        and ME-344;    -   mTOR/PI3K inhibitors, such as gedatolisib, GSK2141795,        omipalisib, and RG6114;    -   Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112,        and SNX5422;    -   Murine double minute (mdm2) oncogene inhibitors, such as        DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);    -   CD137 agonists, such as urelumab, and utomilumab (PF-05082566);    -   STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454,        SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, and SR-8291;    -   FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877,        AZD4547, JNJ-42756493, LY2874455, and Debio-1347;    -   fatty acid synthase (FASN) inhibitors, such as TVB-2640;    -   Anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102),        and IPH-4102;    -   Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, and        inebilizumab;    -   CD44 binders, such as A6;    -   protein phosphatease 2A (PP2A) inhibitors, such as LB-100;    -   CYP17 inhibitors, such as seviteronel (VT-464), ASN-001,        ODM-204, CFG920, and abiraterone acetate;    -   RXR agonists, such as IRX4204;    -   hedgehog/smoothened (hh/Smo) antagonists, such as taladegib, and        patidegib;    -   complement C3 modulators, such as Imprime PGG;    -   IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;    -   EZH2 (enhancer of zeste homolog 2) inhibitors, such as        tazemetostat, CPI-1205, and GSK-2816126;    -   Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy,        HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev        (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir,        LOAd-703, and OBP-301;    -   DOT1L (histone methyltransferase) inhibitors, such as        pinometostat (EPZ-5676);    -   toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,        Bordetella pertussis adenylate cyclase toxin, diphtheria toxin,        and caspase activators;    -   DNA plasmids, such as BC-819    -   PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);    -   WEE1 inhibitors, such as AZD1775 (adavosertib);    -   Rho kinase (ROCK) inhibitors, such as AT13148, and KD025;    -   ERK inhibitors, such as GDC-0994, LY3214996, and MK-8353;    -   IAP inhibitors, such as ASTX660, debio-1143, birinapant,        APG-1387, and LCL-161;    -   RNA polymerase inhibitors, such as lurbinectedin (PM-1183), and        CX-5461;    -   Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin),        OXI-4503, fluorapacin (AC-0001), and plinabulin;    -   Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091,        and PEPA-10;    -   Elongation factor 1 alpha 2 inhibitors, such as plitidepsin;    -   CD95 inhibitors, such as APG-101, APO-010, and asunercept;    -   WT1 inhibitors, such as DSP-7888;    -   splicing factor 3B subunit1 (SF3B1) inhibitors, such as        H3B-8800;    -   PDGFR alpha/KIT mutant-specific inhibitors such as BLU-285;    -   SHP-2 inhibitors, such as TNO155 (SHP-099), and RMC-4550; and    -   retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716;

In some embodiments, provided herein are methods of treating orpreventing a cancer or hyper-proliferative disease in a human or animalhaving or at risk of having the cancer or hyper-proliferative disease isprovided, comprising administering to the human or animal atherapeutically effective amount of a compound of Formula I, II, IIa,IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc,VII, VIIa, VIIb, or VIIc as disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents selected from the group consistingof apoptosis signal-regulating kinase (ASK) inhibitors; Bruton'styrosine kinase (BTK) inhibitors; cluster of differentiation 47 (CD47)inhibitors; cyclin-dependent kinase (CDK) inhibitors; discoidin domainreceptor (DDR) inhibitors; histone deacetylase (HDAC) inhibitors;indoleamine-pyrrole-2,3-dioxygenase (IDO 1) inhibitors; Janus kinase(JAK) inhibitors; lysyl oxidase-like protein (LOXL) inhibitors; matrixmetalloprotease (MMP) inhibitors; mitogen-activated protein kinase (MEK)inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors; spleentyrosine kinase (SYK) inhibitors; toll-like receptor 8 (TLR8)inhibitors; toll-like receptor 9 (TLR9) inhibitors; tyrosine-kinaseinhibitors (TKIs), or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof. Non-limiting examples include:

-   -   Apoptosis Signal-Regulating Kinase (ASK) Inhibitors: ASK        inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors        include, but are not limited to, those described in WO        2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead        Sciences);    -   Bruton's Tyrosine Kinase (BTK) Inhibitors: Examples of BTK        inhibitors include, but are not limited to,        (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,        acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib,        M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008,        spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459,        DTRMWXHS-12, and TAS-5315;    -   Cluster of Differentiation 47 (CD47) inhibitors: Examples of        CD47 inhibitors include, but are not limited to anti-CD47 mAbs        (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002,        CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4),        NI-1701, NI-1801, RCT-1938, and TTI-621;    -   Cyclin-dependent Kinase (CDK) Inhibitors: CDK inhibitors include        inhibitors of CDK 1, 2, 3, 4, 6, 7 and 9, such as abemaciclib,        alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib,        ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib,        selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib,        trilaciclib, and TG-02;    -   Discoidin Domain Receptor (DDR) Inhibitors: DDR inhibitors        include inhibitors of DDR1 and/or DDR2. Examples of DDR        inhibitors include, but are not limited to, those disclosed in        WO 2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda        Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO        2013/027802 (Chugai Pharmaceutical), and WO 2013/034933        (Imperial Innovations);    -   Histone Deacetylase (HDAC) Inhibitors: Examples of HDAC        inhibitors include, but are not limited to, abexinostat,        ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055        (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat,        mocetinostat, panobinostat, pracinostat, quisinostat        (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic        acid (VAL-001), vorinostat, tinostamustine, remetinostat, and        entinostat;    -   Indoleamine-pyrrole-2, 3-dioxygenase (IDO1) inhibitors: Examples        of IDO 1 inhibitors include, but are not limited to, BLV-0801,        epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod,        NKTR-218, NLG-919-based vaccine, PF-06840003,        pyranonaphthoquinone derivatives (SN-35837), resminostat,        SBLK-200802, BMS-986205, and shlDO-ST, EOS-200271, KHK-2455, and        LY-3381916;    -   Janus Kinase (JAK) Inhibitors: JAK inhibitors inhibit JAK1,        JAK2, and/or JAK3. Examples of JAK inhibitors include, but are        not limited to, AT9283, AZD1480, baricitinib, BMS-911543,        fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544),        INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387),        NS-018, pacritinib (SB 1518), peficitinib (ASP015K),        ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and        XL019;    -   Lysyl Oxidase-Like Protein (LOXL) Inhibitors: LOXL inhibitors        include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5.        Examples of LOXL inhibitors include, but are not limited to, the        antibodies described in WO 2009/017833 (Arresto Biosciences).        Examples of LOXL2 inhibitors include, but are not limited to,        the antibodies described in WO 2009/017833 (Arresto        Biosciences), WO 2009/035791 (Arresto Biosciences), and WO        2011/097513 (Gilead Biologics);    -   Matrix Metalloprotease (MMP) Inhibitors: MMP inhibitors include        inhibitors of MMP1 through 10. Examples of MMP9 inhibitors        include, but are not limited to, marimastat (BB-2516),        cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and those        described in WO 2012/027721 (Gilead Biologics);    -   Mitogen-activated Protein Kinase (MEK) Inhibitors: MEK        inhibitors include antroquinonol, binimetinib, cobimetinib        (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib,        trametinib (GSK1120212), uprosertib+trametinib, PD-0325901,        pimasertib, LTT462, AS703988, CC-90003, and refametinib;    -   Phosphatidylinositol 3-kinase (PI3K) Inhibitors: PI3K inhibitors        include inhibitors of PI3Ky, PI3K6, PI3Ki3, PI3Ka, and/or        pan-PI3K. Examples of PI3K inhibitors include, but are not        limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY        10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib),        CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032,        GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib        (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141,        LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604,        rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115,        TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147        (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the        compounds described in WO 2005/113556 (ICOS), WO 2013/052699        (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO        2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead        Calistoga), and WO 2014/201409 (Gilead Sciences);    -   Spleen Tyrosine Kinase (SYK) Inhibitors: Examples of SYK        inhibitors include, but are not limited to,        6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,        BAY-61-3606, cerdulatinib (PRT-062607), entospletinib,        fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343,        tamatinib (R406), GS-9876, and those described in U.S. Pat. No.        8,450,321 (Gilead Connecticut) and those described in U.S.        2015/0175616;    -   Toll-like receptor 8 (TLR8) inhibitors: Examples of TLR8        inhibitors include, but are not limited to, E-6887, IMO-4200,        IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod,        VTX-1463, and VTX-763;    -   Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9        inhibitors include, but are not limited to, AST-008, IMO-2055,        IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042; and    -   Tyrosine-kinase Inhibitors (TKIs): TKIs may target epidermal        growth factor receptors (EGFRs) and receptors for fibroblast        growth factor (FGF), platelet-derived growth factor (PDGF), and        vascular endothelial growth factor (VEGF). Examples of TKIs        include, but are not limited to, afatinib, ARQ-087        (derazantinib), asp5878, AZD3759, AZD4547, bosutinib,        brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib,        dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib,        gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib,        KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin,        nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib,        poziotinib, quizartinib, radotinib, rociletinib, sulfatinib        (HMPL-012), sunitinib, tivoanib, TH-4000, and MEDI-575        (anti-PDGFR antibody).

As used herein, the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy” in the case of treatment with a chemotherapeuticagent) is meant to encompass any non-proteinaceous (i.e., non-peptidic)chemical compound useful in the treatment of cancer. Examples ofchemotherapeutic agents include but are not limited to:

-   -   alkylating agents such as thiotepa and cyclophosphamide        (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and        piposulfan; aziridines such as benzodepa, carboquone,        meturedepa, and uredepa; ethylenimines and methylamelamines        including altretamine, triethyl enemelamine,        triethylenephosphoramide, triethyl enethiophosphoramide, and        trimemylolomelamine; acetogenins, especially bullatacin and        bullatacinone; a camptothecin, including synthetic analog        topotecan; bryostatin, callystatin; CC-1065, including its        adozelesin, carzelesin, and bizelesin synthetic analogs;        cryptophycins, particularly cryptophycin 1 and cryptophycin 8;        dolastatin; duocarmycin, including the synthetic analogs KW-2189        and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; a        sarcodictyin; spongistatin; nitrogen mustards such as        chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide,        evofosfamide, bendamustine, estramustine, ifosfamide,        mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,        novembichin, phenesterine, prednimustine, trofosfamide, and        uracil mustard; nitrosoureas such as carmustine, chlorozotocin,        foremustine, lomustine, nimustine, and ranimustine; antibiotics        such as the enediyne antibiotics (e.g., calicheamicin,        especially calicheamicin gammall and calicheamicin phil1),        dynemicin including dynemicin A, bisphosphonates such as        clodronate, an esperamicin, neocarzinostatin chromophore and        related chromoprotein enediyne antibiotic chromomophores,        aclacinomycins, actinomycin, authramycin, azaserine, bleomycins,        cactinomycin, carabicin, carrninomycin, carzinophilin,        chromomycins, dactinomycin, daunorubicin, detorubicin,        6-diazo-5-oxo-L-norleucine, doxorubicin (including        morpholino-doxorubicin, cyanomorpholino-doxorubicin,        2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin,        esorubicin, idarubicin, marcellomycin, mitomycins such as        mitomycin C, mycophenolic acid, nogalamycin, olivomycins,        peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin,        streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin,        and zorubicin; anti-metabolites such as methotrexate and        5-fluorouracil (5-FU); folic acid analogs such as demopterin,        methotrexate, pteropterin, and trimetrexate; purine analogs such        as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;        pyrimidine analogs such as ancitabine, azacitidine,        6-azauridine, carmofur, cytarabine, dideoxyuridine,        doxifluridine, enocitabine, and floxuridine; androgens such as        calusterone, dromostanolone propionate, epitiostanol,        mepitiostane, and testolactone; anti-adrenals such as        aminoglutethimide, mitotane, and trilostane; folic acid        replinishers such as frolinic acid; radiotherapeutic agents such        as Radium-223; trichothecenes, especially T-2 toxin, verracurin        A, roridin A, and anguidine; taxoids such as paclitaxel        (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel,        BIND-014, tesetaxel; platinum analogs such as cisplatin and        carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide        glycoside; aminolevulinic acid; eniluracil; amsacrine;        hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;        diaziquone; elformthine; elliptinium acetate; an epothilone;        etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin;        lonidamine; maytansinoids such as maytansine and ansamitocins;        mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;        phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic        acid; podophyllinic acid; 2-ethylhydrazide; procarbazine;        polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran;        spirogermanium; tenuazonic acid; trabectedin, triaziquone;        2,2′,2″-tricUorotriemylamine; urethane; vindesine; dacarbazine;        mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;        arabinoside (“Ara-C”); cyclophosphamide; thiopeta; chlorambucil;        gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine;        methotrexate; vinblastine; platinum; etoposide (VP-16);        ifosfamide; mitroxantrone; vancristine; vinorelbine        (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin;        aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase        inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids        such as retinoic acid; capecitabine; NUC-1031; FOLFIRI        (fluorouracil, leucovorin, and irinotecan); and pharmaceutically        acceptable salts, acids, or derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” areanti-hormonal agents such as anti-estrogens and selective estrogenreceptor modulators (SERMs), inhibitors of the enzyme aromatase,anti-androgens, and pharmaceutically acceptable salts, acids orderivatives of any of the above that act to regulate or inhibit hormoneaction on tumors.

Anti-Hormonal Agents

Examples of anti-estrogens and SERMs include, for example, tamoxifen(including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and toremifene(FARESTON®).

Inhibitors of the enzyme aromatase regulate estrogen production in theadrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide,megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole(RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

Examples of anti-androgens include apalutamide, abiraterone,enzalutamide, flutamide, galeterone, nilutamide, bicalutamide,leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

Examples of progesterone receptor antagonist include onapristone.

Anti-Angiogenic Agents

Anti-angiogenic agents include, but are not limited to, retinoid acidand derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®,regorafenib, necuparanib, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism including proline analogs such as 1-azetidine-2-carboxylicacid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,α,α′-dipyridyl, beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3 h)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chicken inhibitor ofmetalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrintetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate,d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin,bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilicacid disodium or “CCA”, thalidomide, angiostatic steroid, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, andinhibitors of S100A9 such as tasquinimod. Other anti-angiogenesis agentsinclude antibodies, preferably monoclonal antibodies against theseangiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms,VEGF-C, HGF/SF, and Ang-1/Ang-2.

Anti-Fibrotic Agents

Anti-fibrotic agents include, but are not limited to, the compounds suchas beta-aminoproprionitrile (BAPN), as well as the compounds disclosedin U.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase andtheir use in the treatment of diseases and conditions associated withthe abnormal deposition of collagen and U.S. Pat. No. 4,997,854 relatingto compounds which inhibit LOX for the treatment of various pathologicalfibrotic states, which are herein incorporated by reference. Furtherexemplary inhibitors are described in U.S. Pat. No. 4,943,593 relatingto compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine,U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and US2004-0248871, which are herein incorporated by reference.

Exemplary anti-fibrotic agents also include the primary amines reactingwith the carbonyl group of the active site of the lysyl oxidases, andmore particularly those which produce, after binding with the carbonyl,a product stabilized by resonance, such as the following primary amines:emylenemamine, hydrazine, phenylhydrazine, and their derivatives;semicarbazide and urea derivatives; aminonitriles such as BAPN or2-nitroethylamine; unsaturated or saturated haloamines such as2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine,3-bromopropylamine, and p-halobenzylamines; and selenohomocysteinelactone.

Other anti-fibrotic agents are copper chelating agents penetrating ornot penetrating the cells. Exemplary compounds include indirectinhibitors which block the aldehyde derivatives originating from theoxidative deamination of the lysyl and hydroxylysyl residues by thelysyl oxidases. Examples include the thiolamines, particularlyD-penicillamine, and its analogs such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate, andsodium-4-mercaptobutanesulphinate trihydrate.

Immunotherapeutic Agents

Examples of immunotherapeutic agents include but are not limited totherapeutic antibodies suitable for treating patients. Some examples oftherapeutic antibodies include abagovomab, ABP-980, adecatumumab,afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab,bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab,brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab,cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab,daratumumab, detumomab, dinutuximab, drozitumab, duligotumab,dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab,ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, andMDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab,lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab,minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab,narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833,obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox,patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab,samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab,tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab,tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab,vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used fortreating indolent B-cell cancers, including marginal-zone lymphoma, WM,CLL and small lymphocytic lymphoma. In some embodiments, a combinationof Rituximab and chemotherapy agents is especially effective.

The exemplified therapeutic antibodies may be further labeled orcombined with a radioisotope particle such as indium-111, yttrium-90(90Y-clivatuzumab), or iodine-131.

Cancer Gene Therapy and Cell Therapy

Cancer gene therapy and cell therapy include the insertion of a normalgene into cancer cells to replace a mutated or altered gene; geneticmodification to silence a mutated gene; genetic approaches to directlykill the cancer cells; including the infusion of immune cells designedto replace most of the patient's own immune system to enhance the immuneresponse to cancer cells, or activate the patient's own immune system (Tcells or Natural Killer cells) to kill cancer cells, or find and killthe cancer cells; and genetic approaches to modify cellular activity tofurther alter endogenous immune responsiveness against cancer.

Gene Editors

Examples of genome editing system include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system.

CAR-T Cell Therapy and TCR-T Cell Therapy

CAR-T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises a tumor antigen-binding domain. The immune effector cell is aT cell or an NK cell. TCR-T cell therapy includes TCR-T cells that areengineered to target tumor derived peptides present on the surface oftumor cells. Cells can be autologous or allogeneic.

In some embodiments, the CAR comprises an antigen binding domain, atransmembrane domain, and an intracellular signaling domain.

In some embodiments, the intracellular domain comprises a primarysignaling domain, a costimulatory domain, or both of a primary signalingdomain and a costimulatory domain.

In some embodiments, the primary signaling domain comprises a functionalsignaling domain of one or more proteins selected from the groupconsisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcRgamma (FCERIG), FcR beta (Fc Epsilon Rlb), CD79a, CD79b, Fcgamma RIIa,DAP10, and DAP12.

In some embodiments, the costimulatory domain comprises a functionaldomain of one or more proteins selected from the group consisting ofCD27, CD28, 4-1BB(CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocytefunction-associated antigen-1 (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, aligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM(LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta,IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4,CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 ld, ITGAE, CD103, ITGAL, CD 1la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18,LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4),CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1,CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMFi, CD150,IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76,PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D.

In some embodiments, the transmembrane domain comprises a transmembranedomain of a protein selected from the group consisting of the alpha,beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4,CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137,CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD1 la, CD18), ICOS (CD278),4-1BB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1),CD160, CD19, IL2R beta, IL2R gamma, IL7R u, ITGA1, VLA1, CD49a, ITGA4,IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 ld, ITGAE, CD103, ITGAL, CD1la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18,LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100(SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMFi, CD150, IPO-3), BLAME(SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, andNKG2C.

In some embodiments, the antigen binding domain binds a tumor antigen.

In some embodiments, the tumor antigen is selected from the groupconsisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to asCD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-likemolecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptorvariant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3(aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); TNF receptor familymember B cell maturation (BCMA); Tn antigen ((Tn Ag) or(GaINAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptortyrosine kinase-like orphan receptor 1 (RORI); Fms-Like, Tyrosine Kinase3 (FLT3); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6;Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule(EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunitalpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha(IL-11Ra); prostate stem cell antigen (PSCA); Protease Serine21(Testisin or PRSS21); vascular endothelial growth factor receptor 2(VEGFR2); Lewis(Y)antigen; CD24; Platelet-derived growth factor receptorbeta (PDGFR-beta); Stage-specificembryonic antigen-4 (SSEA-4); CD20;delta like 3 (DLL3); Folate receptor alpha; Receptor tyrosine-proteinkinase, ERBB2 (Her2/neu); Mucin 1, cell surface associated (MUC1);epidermal growth factor receptor (EGFR); neural cell adhesion molecule(NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP);insulin-like growth factor 1 receptor (IGF-I receptor), carbonicanhydrase IX (CAIX); Proteasome (Prosome, Macropain) Subunit, Beta Type,9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consistingof breakpoint cluster region (BCR) and Abelson murineleukemia viraloncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2(EphA2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); gangliosideGM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5);high molecular weight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1(TEM1/CD248); tumor endothelial marker 7-related (TEM7R); sixtransmembrane epithelial antigen of the prostate I (STEAP1); claudin 6(CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupledreceptor class C group 5, member D (GPRCSD); chromosome X open readingframe 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK);Polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion ofgloboH glycoceramide (GloboH); mammary gland differentiation antigen(NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1(HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); Gprotein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locusK 9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCR Gamma AlternateReading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer/testisantigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-la);Melanomaassociated antigen 1 (MAGE-A1); ETS translocation-variant gene6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); XAntigen Family, Member 1A (XAGE1); angiopoietin-binding cell surfacereceptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanomacancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor proteinp53, (p53); p53 mutant; prostein; survivin; telomerase; prostatecarcinoma tumor antigen-1 (PCTA-1 or Galectin 8), melanoma antigenrecognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant;human Telomerase reverse transcriptase (hTERT); sarcoma translocationbreakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG(transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetylglucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3);Androgen receptor; Cyclin B1; v-myc avian myelocytomatosis viraloncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family MemberC (RhoC); Tyrosinase-related protein 2 (TRP-2); Cytochrome P450 1B1(CYPIBI); CCCTC-Binding Factor (Zinc Finger Protein)-Like (BORIS or Brotherof the Regulator of Imprinted Sites), Squamous Cell Carcinoma AntigenRecognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5);proacrosin binding protein sp32 (OY-TES I); lymphocyte-specific proteintyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovialsarcoma, X breakpoint 2 (SSX2); Receptor for Advanced GlycationEndproducts (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2(RU2); legumain; human papilloma virus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associatedimmunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor(FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily Amember 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-typelectin domain family 12 member A (CLEC12A); bone marrow stromal cellantigen 2 (BST2); EGF-like modulecontaining mucin-like hormonereceptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3);Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1(IGLL1).

In some embodiments, the tumor antigen is selected from CD150, 5T4,ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148,CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261,CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5,CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1,CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2,ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 in combination, HER2-HER3 incombination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelopeglycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2/neu, IGF-1R,IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii,L1-CAM, L1-cell adhesion molecule, Lewis Y, L1-CAM, MAGE A3, MAGE-A1,MART-I, MUC1, NKG2C ligands, NKG2D Ligands, NYESO-1, OEPHa2, PIGF, PSCA,PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-Ri (DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor,alphafetoprotein (AFP), an angiogenesis factor, an exogenous cognatebinding molecule (ExoCBM), oncogene product, anti-folate receptor,c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2,epithelial tumor antigen, estrogen receptor, fetal acethycholine ereceptor, folate binding protein, gp100, hepatitis B surface antigen,kappa chain, kappa light chain, kdr, lambda chain, livin,melanoma-associated antigen, mesothelin, mouse double minute 2 homolog(MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens,oncofetal antigen, ROR2, progesterone receptor, prostate specificantigen, tEGFR, tenascin, P2-Microgiobuiin, and Fc Receptor-like 5(FcRL5).

Non limiting examples of cell therapies include Algenpantucel-L,Sipuleucel-T, (BPX-501) rivogenlecleucel U.S. Pat. No. 9,089,520,WO2016100236, AU-105, ACTR-087, activated allogeneic natural killercells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007,UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema,FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells,CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22cells, EGFRt/19-28z/4-1BBL CAR T cells, autologous 4H11-28z/fIL-12/EFGRtT cell, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T,Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503,CMD-504, CMD-502,CMD-601,CMD-602, and CSG-005.

In some embodiments, the tumor targeting antigen includes:Alpha-fetoprotein, such as ET-1402, and AFP-TCR; Anthrax toxin receptor1, such as anti-TEM8 CAR T-cell therapy; B cell maturation antigens(BCMA), such as bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998,LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101,and AUTO-2 (APRIL-CAR); Anti-CLL-1 antibodies, such as KITE-796; B7homolog 6, such as CAR-NKp30 and CAR-B7H6; B-lymphocyte antigen CD19,such as TBI-1501, CTL-119 huCART-19 T cells, JCAR-015 U.S. Pat. No.7,446,190, JCAR-014, JCAR-017, (WO2016196388, WO2016033570,WO2015157386), axicabtagene ciloleucel (KTE-C19), U.S. Pat. Nos.7,741,465, 6,319,494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019),WO2012079000, WO2017049166, CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcells, CD19/4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19,CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, and IM19 CAR-T;B-lymphocyte antigen CD20, such as ATTCK-20; B-lymphocyte cell adhesion,such as UCART-22, and JCAR-018 (WO2016090190); NY-ESO-1, such asGSK-3377794, and TBI-1301; Carbonic anhydrase, such as DC-Ad-GMCAIX;Caspase 9 suicide gene, such as CaspaCIDe DLI, and BPX-501; CCR5, suchas SB-728; CDw123, such as MB-102, and UCART-123; CD20m such asCBM-C20.1; CD4, such as ICG-122; CD30, such as CART30 (CBM-C30.1); CD33,such as CIK-CAR.CD33; CD38, such as T-007, and UCART-38; CD40 ligand,such as BPX-201; CEACAM protein 4 modulators, such as MG7-CART; Claudin6, such as CSG-002; EBV targeted, such as CMD-003; EGFR, such asautologous 4H11-28z/fIL-12/EFGRt T cell; Endonuclease, such as PGN-514,and PGN-201; Epstein-Barr virus specific T-lymphocytes, such as TT-10;Erbb2, such as CST-102 and CIDeCAR; Ganglioside (GD2), such as4SCAR-GD2; Glutamate carboxypeptidase II, such as CIK-CAR.PSMA,CART-PSMA-TGFBRDN, and P-PSMA-101; Glypican-3(GPC3), such as TT-16 andGLYCAR; Hemoglobin, such as PGN-236; Hepatocyte growth factor receptor,such as anti-cMet RNA CAR T; Human papillomavirus E7 protein, such asKITE-439; Immunoglobulin gamma Fc receptor III, such as ACTRO87; IL-12,such as DC-RTS-IL-12; IL-12 agonist/mucin 16, such as JCAR-020; IL-13alpha 2, such as MB-101; IL-2, such as CST-101; K-Ras GTPase, such asanti-KRAS G12V mTCR cell therapy; Neural cell adhesion molecule L1 L1CAM(CD171), such as JCAR-023; Latent membrane protein 1/Latent membraneprotein 2, such as Ad5f35-LMPdl-2-transduced autologous dendritic cells;Melanoma associated antigen 10, such as MAGE-A10C796T and MAGE-A10 TCR;Melanoma associated antigen 3/Melanoma associated antigen 6 (MAGE A3/A6)such as KITE-718; Mesothelin, such as CSG-MESO and TC-210; NKG2D, suchas NKR-2; Ntrkrl tyrosine kinase receptor, such as JCAR-024; T cellreceptors, such as BPX-701 and IMCgp100; T-lymphocyte, such as TT-12;Tumor infiltrating lymphocytes, such as LN-144 and LN-145; and Wilmstumor protein, such as JTCR-016, WT1-CTL.

Lymphoma or Leukemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating lymphoma or leukemia. These agents include aldesleukin,alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10,antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib(VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, bulsulfan,campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine,caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide,doxorubicin, vincristine, and prednisone), cisplatin, cladribine,clofarabine, curcumin, CVP (cyclophosphamide, vincristine, andprednisone), cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin,doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide,cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin,epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine,cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide,and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR(fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD(hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide,carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride,interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013),lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, andprednisolone), melphalan, mesna, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fattyacids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib(PD0332991), pegfilgrastim, PEGylated liposomal doxorubicinhydrochloride, perifosin, prednisolone, prednisone, recombinant flt3ligand, recombinant human thrombopoietin, recombinant interferon alfa,recombinant interleukin-11, recombinant interleukin-12, rituximab,R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximaband FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP),R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate,simvastatin, sirolimus, styryl sulphones, tacrolimus, tanespimycin,temsirolimus (CC₁₋₇₇9), thalidomide, therapeutic allogeneic lymphocytes,thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbineditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, andhydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

One modified approach is radioimmunotherapy, wherein a monoclonalantibody is combined with a radioisotope particle, such as indium-111,yttrium-90, and iodine-131. Examples of combination therapies include,but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

The above-mentioned therapies can be supplemented or combined with stemcell transplantation or treatment. Therapeutic procedures includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechnique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and non-myeloablative allogeneichematopoietic stem cell transplantation.

Non-Hodgkin's Lymphomas Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating non-Hodgkin's lymphomas (NHL), especially those of B cellorigin, which include monoclonal antibodies, standard chemotherapyapproaches (e.g., CHOP, CVP, FCM, MCP, and the like),radioimmunotherapy, and combinations thereof, especially integration ofan antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies for the treatment ofNHL/B-cell cancers include rituximab, alemtuzumab, human or humanizedanti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducingligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, andanti-CD74.

Examples of experimental antibody agents used in treatment of NHL/B-cellcancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab,SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab,and bevacizumab.

Examples of standard regimens of chemotherapy for NHL/B-cell cancersinclude CHOP, FCM, CVP, MCP, R—CHOP, R—FCM, R-CVP, and R-MCP.

Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

Mantle Cell Lymphoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating mantle cell lymphoma (MCL), which include combinationchemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can alsobe supplemented with the monoclonal antibody rituximab to formcombination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of theabove-mentioned therapies may be combined with stem cell transplantationor ICE in order to treat MCL.

Other examples of therapeutic agents suitable for treating MCL include:

-   -   immunotherapy, such as monoclonal antibodies (like rituximab)        and cancer vaccines, such as GTOP-99, which are based on the        genetic makeup of an individual patient's tumor;    -   radioimmunotherapy, wherein a monoclonal antibody is combined        with a radioisotope particle, such as iodine-131 tositumomab        (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and        BEXXAR® in sequential treatment with CHOP;    -   autologous stem cell transplantation coupled with high-dose        chemotherapy, administering proteasome inhibitors such as        bortezomib (VELCADE® or PS-341), or administering        antiangiogenesis agents such as thalidomide, especially in        combination with rituximab;    -   drugs that lead to the degradation of Bcl-2 protein and increase        cancer cell sensitivity to chemotherapy, such as oblimersen, in        combination with other chemotherapeutic agents;    -   mTOR inhibitors, which can lead to inhibition of cell growth and        even cell death. Non-limiting examples are sirolimus,        temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126,        PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus        in combination with RITUXAN®, VELCADE®, or other        chemotherapeutic agents;    -   other agents such as flavopiridol, palbociclib (PD0332991),        R-roscovitine (selicicilib, CYC202), styryl sulphones, obatoclax        (GX15-070), TRAIL, Anti-TRAIL death receptors DR4 and DR5        antibodies, temsirolimus (TORISEL®, CCl-779), everolimus        (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide        (REVLIMID®, CC-5013), and geldanamycin (17-AAG).

Waldenstrom's Macroglobulinemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating Waldenstrom's Macroglobulinemia (WM), which includealdesleukin, alemtuzumab, alvocidib, amifostine trihydrate,aminocamptothecin, antineoplaston A10, antineoplaston AS2-1,anti-thymocyte globulin, arsenic trioxide, autologous humantumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, betaalethine, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H,carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin,clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicinhydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab(hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide,filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibodyMN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone,lymphokine-activated killer cells, melphalan, mesna, methotrexate,mitoxantrone hydrochloride, monoclonal antibody CD19 (such astisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20,motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen,octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel,pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride,pentostatin, perifosine, prednisone, recombinant flt3 ligand,recombinant human thrombopoietin, recombinant interferon alfa,recombinant interleukin-11, recombinant interleukin-12, rituximab,sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus,tacrolimus, tanespimycin, thalidomide, therapeutic allogeneiclymphocytes, thiotepa, tipifarnib, tositumomab, veltuzumab, vincristinesulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptidevaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan,yttrium-90 humanized epratuzumab, and any combinations thereof.

Other examples of therapeutic procedures used to treat WM includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and nonmyeloablative allogeneichematopoietic stem cell transplantation.

Diffuse Large B-Cell Lymphoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating diffuse large B-cell lymphoma (DLBCL), which includecyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20monoclonal antibodies, etoposide, bleomycin, many of the agents listedfor WM, and any combination thereof, such as ICE and R-ICE.

Chronic Lymphocytic Leukemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating chronic lymphocytic leukemia (CLL), which include chlorambucil,cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin,vincristine, prednisone, prednisolone, alemtuzumab, many of the agentslisted for WM, and combination chemotherapy and chemoimmunotherapy,including the following common combination regimens: CVP, R-CVP, ICE,R-ICE, FCR, and FR.

Myelofibrosis Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating myelofibrosis, which include hedgehog inhibitors, histonedeacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors.Non-limiting examples of hedgehog inhibitors are saridegib andvismodegib.

Examples of HDAC inhibitors include, but are not limited to, pracinostatand panobinostat.

Non-limiting examples of tyrosine kinase inhibitors includelestaurtinib, bosutinib, imatinib, gilteritinib, radotinib, andcabozantinib.

Hyperproliferative Disease Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating a hyper-proliferative disease, which include gemcitabine,nab-paclitaxel, and gemcitabine/nab-paclitaxel with a JAK inhibitorand/or PI3Kδ inhibitor.

Bladder Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating bladder cancer, which include atezolizumab, carboplatin,cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine,idosfamide, Interferon alfa-2b, methotrexate, mitomycin, nab-paclitaxel,paclitaxel, pemetrexed, thiotepa, vinblastine, and any combinationsthereof.

Breast Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating breast cancer, which include albumin-bound paclitaxel,anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide,docetaxel, doxorubicin, epirubicin, everolimus, exemestane,fluorouracil, fulvestrant, gemcitabine, Ixabepilone, lapatinib,Letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomaldoxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab,vinorelbine, and any combinations thereof.

Triple Negative Breast Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating triple negative breast cancer, which include cyclophosphamide,docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, andcombinations thereof.

Colorectal Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating colorectal cancer, which include bevacizumab, capecitabine,cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin,panitumumab, ziv-aflibercept, and any combinations thereof.

Castration-Resistant Prostate Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating castration-resistant prostate cancer, which includeabiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone,sipuleucel-T, and any combinations thereof.

Esophageal and Esophagogastric Junction Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating esophageal and esophagogastric junction cancer, which includecapecitabine, carboplatin, cisplatin, docetaxel, epirubicin,fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin,paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Gastric Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating gastric cancer, which include capecitabine, carboplatin,cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil,Irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab,trastuzumab, and any combinations thereof.

Head & Neck Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating head & neck cancer, which include afatinib, bleomycin,capecitabine, carboplatin, cetuximab, cisplatin, docetaxel,fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab,paclitaxel, pembrolizumab, vinorelbine, and any combinations thereof.

Hepatobiliary Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating hepatobiliary cancer, which include capecitabine, cisplatin,fluoropyrimidine, 5-fluorourcil, gemecitabine, oxaliplatin, sorafenib,and any combinations thereof.

Hepatocellular Carcinoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating hepatocellular carcinoma, which include capecitabine,doxorubicin, gemcitabine, sorafenib, and any combinations thereof.

Non-Small Cell Lung Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating non-small cell lung cancer (NSCLC), which include afatinib,albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab,cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel,erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab,pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib,vemurafenib, vinblastine, vinorelbine, and any combinations thereof.

Small Cell Lung Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating small cell lung cancer (SCLC), which include bendamustime,carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin,etoposide, gemcitabine, ipillimumab, irinotecan, nivolumab, paclitaxel,temozolomide, topotecan, vincristine, vinorelbine, and any combinationsthereof.

Melanoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating melanoma, which include albumin bound paclitaxel, carboplatin,cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib,interferon alfa-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel,pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib,vinblastine, and any combinations thereof.

Ovarian Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating ovarian cancer, which include 5-flourouracil, albumin boundpaclitaxel, altretamine, anastrozole, bevacizumab, capecitabine,carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin,etoposide, exemestane, gemcibabine, ifosfamide, irinotecan, letrozole,leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan,olaparib, oxaliplatin, paclitaxel, Pazopanib, pemetrexed, tamoxifen,topotecan, vinorelbine, and any combinations thereof.

Pancreatic Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating pancreatic cancer, which include 5-fluorourcil, albumin-boundpaclitaxel, capecitabine, cisplatin, docetaxel, erlotinib,fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin,paclitaxel, and any combinations thereof.

Renal Cell Carcinoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating renal cell carcinoma, which include axitinib, bevacizumab,cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib,sorafenib, sunitinib, temsirolimus, and any combinations thereof.

VII. Compound Preparation

Some embodiments of the present disclosure are directed to processes andintermediates useful for preparing the compounds provided herein orpharmaceutically acceptable salts thereof.

Compounds described herein can be purified by any of the means known inthe art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography.

During any of the processes for preparation of the compounds providedherein, it may be necessary and/or desirable to protect sensitive orreactive groups on any of the molecules concerned. This may be achievedby means of conventional protecting groups as described in standardworks, such as T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” 4^(th) ed., Wiley, New York 2006. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used.

The methods of the present disclosure generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordisatereomerically pure.

Representative syntheses of compounds of the present disclosure aredescribed in the schemes below, and the particular examples that follow.

LIST OF ABBREVIATIONS AND ACRONYMS Abbreviation Meaning ° C. DegreeCelsius Ac Acetyl ACN or MeCN Acetonitrile

AcOH Acetic acidaq. Aqueous

Ar Argon

ATP Adenosine triphosphateBoc tert-butyloxycarbonyl

br Broad

ca circaCH(OCH₃)₃ Trimethyl orthoformatec-Pr or c-propyl cyclopropylCy cyclohexyld Doublet or deuterated

DCE Dichloroethene

DCM or CH₂Cl₂ Dichloromethanedd Doublet of doublets

DIEA or DIPEA Diisopropylethylamine DMAc or DMA Dimethylacetamide DMAPDimethylaminopyridine DMF Dimethylformamide DMSO Dimethylsulfoxide DMEDimethoxyethane dt Doublet-triplet eq Equivalents

ES/MS Electrospray mass spectrometry

Et Ethyl

EA or EtOAc Ethyl acetate

g Grams

HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphateHCOOH Formic acid

Hex Hexanes

HPLC High pressure liquid chromatography

hr or h or hrs Hours Hz Hertz

IPA Isopropyl alcoholi-pr or i-Pr IsopropylJ Coupling constant (MHz)K₂CO₃ Potassium carbonate

Kg or kg Kilogram L Liter

LCMS or LC-MS Liquid chromatography-mass spectrometry

M Molar

m multipletM+ Mass peakM+H+ Mass peak plus hydrogen

Me Methyl MeOH Methanol mg Milligram MHz Megahertz ml or mL MillilitermM Millimolar

mmol Millimole

mol Mole

MS Mass spectroscopyMs methanesulfonyl

N Normal

NaH Sodium hydriden-Bu or Bu Butyl

NH₄Cl Ammonium Chloride

NMR Nuclear magnetic resonance

NMP N-methylpyrrolidinone Pd—C/Pd/C Palladium on Carbon

Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladiumPE Petroleum ether

Ph Phenyl q Quartet

RP Reverse phaseRT or rt Room temperature

s Singlet

sat. or satd. Saturatedsec second(s)sec-Bu sec-Butyl

t Triplet

T3P Propylphosphonic anhydride solution

TEA Triethylamine

t-Bu or tert-Bu or t-butyl tert-ButylTFA Trifluoroacetic acidTfOH Triflic acid

THF Tetrahydrofuran

TR-FRET Time-resolved fluorescence energy transfer

wt Weight

δ Chemical shift (ppm)

μL or μl Microliter μM Micromolar General Synthetic Schemes

General Reaction Schemes I, II, III, IV, V, VI, VII, VIII, and IX areprovided as further embodiments of the present disclosure and illustrategeneral methods which were used to prepare certain compounds of thepresent disclosure and which can be used to prepare additional compoundsof the present disclosure. Each of the variables (e.g., R¹, R², R³, R⁴)of formulas (1)-(27) are as defined herein.

The compounds of the present disclosure may be prepared using themethods disclosed herein and routine modifications thereof, which willbe apparent to a skilled artisan given the disclosure herein and methodswell known in the art. Conventional and well-known synthetic methods maybe used in addition to the teachings herein. The synthesis of typicalcompounds described herein may be accomplished as described in thefollowing examples. If available, reagents may be purchasedcommercially, e.g., from Sigma Aldrich or other chemical suppliers. Ingeneral, compounds described herein are typically stable and isolatableat room temperature and pressure. The compounds prepared herein can bepurified using the methods known to the person of ordinary skill in theart, including those described herein. A skilled artisan will appreciatethat when acids (e.g., TFA) are present in purification solvents, thenthe final product may be isolated as a salt (for e.g., TFA salt).

Typical embodiments of compounds disclosed herein may be synthesizedusing the general reaction schemes described below. It will be apparentto a skilled artisan given the description herein that the generalschemes may be altered by substitution of the starting materials withother materials having similar structures to result in products that arecorrespondingly different. Descriptions of syntheses follow to providenumerous examples of how the starting materials may vary to providecorresponding products. Given a desired product for which thesubstituent groups are defined, the necessary starting materialsgenerally may be determined by inspection. Starting materials aretypically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodimentsdisclosed in the present disclosure, inspection of the structure of thecompound to be synthesized will provide the identity of each substituentgroup. The identity of the final product will generally render apparentthe identity of the necessary starting materials by a simple process ofinspection, given the examples herein.

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, and the like). Unless specified to the contrary, the solventsused in the reactions of the present disclosure are inert organicsolvents, and the reactions are carried out under an inert gas,preferably nitrogen or argon.

Reaction Scheme I

The compounds of Formula I may be prepared using the methods similar tothe Reaction Scheme I shown below.

Step 1—Preparation of a Compound of Formula (3)

The compounds of formula (3) can be made by combining compounds (1) and(2). Compounds (1) and (2) are commercially available or can be made bymethods known in the art. Compounds (1) and (2) can be mixed in asuitable solvent such as THF. After stirring at a temperature between 0OC and 100 OC for between 10 min and 24 h or until reaction is complete,the reaction is allowed to cool to room temperature. The compound offormula (3) can be obtained by filtration or precipitation.

Step 2—Preparation of a Compound of Formula (4)

The compounds of formula (4) may be prepared by chlorination of thecompounds of formula (3) by methods known in the art. A compound offormula (3) may be mixed with POCl₃ in a suitable solvent such astoluene. After stirring at a temperature between 0° C. and 100° C. forbetween 10 min and 24 h or until reaction is complete, the reaction isallowed to cool to room temperature. The solvent can then be removedunder reduced pressure. To extract the compound of formula (4), anorganic solvent such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated to obtainthe compound of formula (4). The compound of formula (4) may be purifiedby any suitable methods known in the art such as chromatography onsilica gel, trituration, precipitation, or crystallization.

Step 3—Preparation of a Compound of Formula (5)

The compounds of formula (5) may be prepared by reduction of thecompounds of formula (4) by methods known in the art. A compound offormula (4) can be mixed with Zinc dust and ammonium chloride insuitable solvent such as THF, MeOH, or water, or a mixture of solventconsisting of THF, MeOH, and water. After stirring at a temperaturebetween 0° C. and 100° C. for between 1 h and 24 h or until reaction iscomplete, the reaction is allowed to cool to room temperature andfiltered through celite bed. To extract the compound of formula (5), anorganic solvent such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated to obtainthe compound of formula (5). The compound of formula (5) may be purifiedby any suitable methods known in the art such as chromatography onsilica gel, trituration, precipitation, or crystallization.

Step 4—Preparation of a Compound of Formula (6)

The compounds of formula (6) may be prepared by cyclization of thecompounds of formula (5) by methods known in the art. A compound offormula (5) can be mixed with trimethyl orthoformate and formic acid.After stirring at a temperature between 0° C. and 100° C. for between 1h and 24 h or until reaction is complete, the remaining solvent isremoved via distillation. To extract the compound of formula (6), anorganic solvent such as dichloromethane may be added, followed bywashing with water and brine. The organic phase can be concentrated toobtain the compound of formula (6). The compound of formula (6) may bepurified by any suitable methods known in the art such as chromatographyon silica gel, trituration, precipitation, crystallization, or washingwith organic solvent such as ether including but not limited to methylt-butyl ether.

Step 5—Preparation of a Compound of Formula (7)

The compounds of formula (7) may be prepared by fluorination of thecompounds of formula (6) by methods known in the art. A compound offormula (6) can be mixed with cesium fluoride in a solvent such DMF.After stirring at a temperature between room temperature and 110° C. forbetween 1 h and 24 h or until reaction is complete, the reaction iscooled to between 0° C. and room temperature by adding ice water or byadding the reaction mixture to ice water. To extract the compound offormula (7), an organic solvent such as ethyl acetate may be added,followed by washing with water and brine. The organic phase can beconcentrated to obtain the compound of formula (7). The compound offormula (7) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation, orcrystallization.

Step 6—Preparation of a Compound of Formula (9)

The compounds of formula (9) can be made by combining compounds offormulas (6) and (8) or combining compounds of formulas (7) and (8) bymethods known in the art. Compounds of formula (8) are commerciallyavailable or can be made by methods known in the art. A compound offormula (8) can be mixed with either compounds of formula (6) or (7) inthe presence of a base such as sodium hydride in a suitable solvent suchas NMP or DMA. After stirring at a temperature between room temperatureand 100° C. for between 1 h and 24 h or until reaction is complete, thereaction can be added to water and treated with acid such as 10% citricacid. The compound of formula (7) may be obtained by filtration orprecipitation.

Step 7—Preparation of a Compound of Formula (12)

The compounds of formula (12) can be made by combining compounds offormulas (10) and (11) by methods known in the art. Compounds offormulas (10) and (11) are commercially available or can be made bymethods known in the art. Compounds of formulas (10) and (11) can bemixed in the presence of a base such as potassium carbonate in asuitable solvent such as DMF. After stirring at a temperature betweenroom temperature and 50° C. for between 1 h and 24 h or until reactionis complete, the reaction is cooled to room temperature. To extract thecompound of formula (12), an organic solvent such as ethyl acetate maybe added, followed by washing with water and brine. The organic phasecan be concentrated to obtain the compound of formula (12). The compoundof formula (12) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation, orcrystallization.

Step 8—Preparation of a Compound of Formula (13)

The compounds of formula (13) may be prepared by reductive amination ofthe compounds of formula (12) by methods known in the art. Compounds offormula (12) and amines, that are commercially available or synthesizedby methods known in the art, can be mixed with a reducing agent such assodium triacetoxy borohydride or sodium cyanoborohydride in the presenceof acid, such as acetic acid, or Lewis acid, such as zinc chloride, in asuitable solvent such as dichloroethane or methanol. After stirring at atemperature between 0° C. and room temperature for between 1 h and 24 hor until reaction is complete, the reaction may be added to aqueoussolution such as saturated aqueous sodium bicarbonate solution. Toextract the compound of formula (13), an organic solvent such asmethylene chloride may be added, followed by washing with water andbrine. The organic phase can be concentrated to obtain the compound offormula (13). The compound of formula (13) may be purified by anysuitable methods known in the art such as chromatography on silica gel,trituration, precipitation, or crystallization.

Step 9—Preparation of a Compound of Formula I

The compounds of Formula I can be made by combining the compounds offormula (9) and compounds of formula (13) by methods known in the art.Compounds of formulas (9) and (13) can be mixed in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium and a base suchas cesium carbonate, sodium carbonate, or potassium phosphate tribasicin a suitable solvent such as a mixture of dimethoxyethane and water, ora mixture of DMAc and water. After stirring at a temperature between 50°C. and 150° C. for between 1 and 24 hours, the reaction is allowed tocool to room temperature. Compounds of Formula I may be filtered andconcentrated under reduced pressure. To extract the compound of FormulaI, an organic solvent such as methylene chloride may be added, followedby washing with water and brine. The organic phase can be concentratedto obtain the compound of Formula I. The compound of Formula I may bepurified by any suitable methods known in the art such as chromatographyon silica gel, reverse phase chromatography, trituration, precipitation,or crystallization.

Reaction Scheme II

The compounds of Formula I may be prepared using the alternate methodssimilar to the Reaction Scheme II shown below.

Step 1—Preparation of a Compound of Formula (14)

The compounds of formula (14) can be made by combining the compounds offormulas (6) and (13) by methods known in the art. Compounds of formulas(9) and (13) can be mixed in the presence of a catalyst such astetrakis(triphenylphosphine)palladium and a base such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic in asuitable solvent such as a mixture of dimethoxyethane and water, or amixture of DMAc and water. After stirring at a temperature between 50°C. and 150° C. for between 1 and 24 hours, the reaction is allowed tocool to room temperature. Compounds of formula (14) may be filtered andconcentrated under reduced pressure. To extract the compound of formula(14), an organic solvent such as methylene chloride may be added,followed by washing with water and brine. The organic phase can beconcentrated to obtain the compound of formula (14). The compound offormula (14) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, reverse phase chromatography,trituration, precipitation, or crystallization.

Step 2—Preparation of a Compound of Formula I

The compounds of Formula I can be made by combining the compounds offormulas (8) and (14) by methods known in the art. Compounds of formulas(8) and (14) can be mixed in the presence of a catalyst such astris(dibenzylideneacetone)dipalladium, a ligand such as xantphos, and abase such as cesium carbonate in a suitable solvent such as dioxane.After stirring at a temperature between 50° C. and 150° C. for between 1and 24 hours, the reaction is allowed to cool to room temperature.Compounds of Formula I may be filtered and concentrated under reducedpressure. To extract the compound of Formula I, an organic solvent suchas methylene chloride may be added, followed by washing with water andbrine. The organic phase can be concentrated to obtain the compound ofFormula I. The compound of Formula I may be purified by any suitablemethods known in the art such as chromatography on silica gel, reversephase chromatography, trituration, precipitation, or crystallization.

Reaction Scheme III

The compounds of Formula I may be prepared using the alternate methodssimilar to the Reaction Scheme III shown below.

Step 1—Preparation of a Compound of Formula (15)

The compounds of formula (15) can be made by amination of compounds offormula (6) by methods known in the art. A compound of formula (6) canbe mixed with ammonium hydroxide solution in a suitable solvent such asN-methylpyrrolidone. After stirring at a temperature between 50° C. and150° C. for between 1 and 48 hours, the reaction is allowed to cool toroom temperature. Compounds of formula (15) may be added to water andfurther cooled to 0° C. while stirring. The compound of formula (15) maybe isolated by any suitable methods known in the art, such as filtrationor precipitation.

Step 2—Preparation of a Compound of Formula (16)

The compounds of formula (16) can be made by combining the compounds offormulas (13) and (15) by methods known in the art. Compounds of formula(13) and (15) can be mixed in the presence of a catalyst such astetrakis(triphenylphosphine)palladium and a base such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic in asuitable solvent such as a mixture of dimethoxyethane and water, amixture of dimethylacetamide and water, or a mixture ofdimethylformamide, dimethoxyethane, and water. After stirring at atemperature between 50° C. and 150° C. for between 1 and 24 hours, thereaction is allowed to cool to room temperature. Compounds of formula(16) may be filtered and concentrated under reduced pressure. To extractthe compound of formula (16), an organic solvent such as methylenechloride may be added, followed by washing with water and brine. Theorganic phase can be concentrated to obtain the compound of formula(16). The compound of formula (16) may be purified by any suitablemethods known in the art such as chromatography on silica gel, reversephase chromatography, trituration, precipitation, or crystallization.

Step 3—Preparation of a Compound of Formula I

The compounds of Formula I can be made by combining the compounds offormulas (16) and (20) by methods known in the art. Compounds offormulas (16) and (20) can be mixed in the presence of a catalyst suchas tris(dibenzylideneacetone)dipalladium, a ligand such as xantphos, anda base such as cesium carbonate in a suitable solvent such as dioxane.After stirring at a temperature between 50° C. and 150° C. for between 1and 24 hours, the reaction is allowed to cool to room temperature.Compounds of Formula I may be filtered and concentrated under reducedpressure. To extract the compound of Formula I, an organic solvent suchas methylene chloride may be added, followed by washing with water andbrine. The organic phase can be concentrated to obtain the compound ofFormula I. The compound of Formula I may be purified by any suitablemethods known in the art such as chromatography on silica gel, reversephase chromatography, trituration, precipitation, or crystallization.

Reaction Scheme IV

The compounds of formula (I-B) may be prepared using the methods similarto the Reaction Scheme IV shown below.

Step 1—Preparation of a Compound of Formula (18)

The compounds of formula (18) can be made by removing thetert-butyloxycarbonyl protecting group of compounds of formula (17) bymethods known in the art. A compound of formula (17) can be mixed withan acidic solution such as 4M hydrochloric acid solution in a suitablesolvent such as dichloromethane or dioxane. After stirring at roomtemperature for between 10 minutes and 24 h, the solvent is evaporatedin vacuo. The compound of formula (18) may be isolated by any suitablemethods known in the art, such as filtration, trituration, orprecipitation.

Step 2—Preparation of a Compound of Formula (I-B)

The compounds of formula (I-B) can be made by reductive amination oramide synthesis of compounds of formula (18) by methods known in theart. Compounds of formula (18) can be mixed with amines, that arecommercially available or synthesized by methods known in the art, oracid chlorides, that are commercially available or synthesized bymethods known in the art, or carboxylic acids, that are commerciallyavailable or synthesized by methods known in the art, in the presence ofa reducing agent such as sodium triacetoxy borohydride or sodiumcyanoborohydride with an acid, such as acetic acid, or a Lewis acid,such as zinc chloride, in a suitable solvent such as dichloroethane ormethanol, or in the presence of a coupling reagent such as HATU orpropylphosphonic anhydride solution in a suitable solvent such asacetonitrile, dimethylformamide, and dichloroethane. After stirring at atemperature between 0° C. and 100° C. for between 1 h and 24 h, thereaction may be added to aqueous solution such as saturated aqueoussodium bicarbonate solution. To extract the compound of formula (I-B),an organic solvent such as ethyl acetate or methylene chloride may beadded, followed by washing with water and brine. The organic phase canbe concentrated to obtain the compound of formula (I-B). The compound offormula (I-B) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation, orcrystallization.

Reaction Scheme V

The compounds of formula (21) may be prepared using the alternatemethods similar to the Reaction Scheme V shown below.

Step 1—Preparation of a Compound of Formula (20)

The compounds of formula (20) can be made by combining the compounds offormulas (19) and (12) by methods known in the art. With respect tocompounds (20), R⁷ and G are as defined herein. Compounds of formulas(19) and (12) can be mixed in the presence of a catalyst, such astetrakis(triphenylphosphine)palladium, and a base such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic, in asuitable solvent, such as a mixture of dimethoxyethane and water, amixture of dimethylacetamide and water, or a mixture ofdimethylformamide, dimethoxyethane, and water. After stirring at atemperature between 50° C. and 150° C. for between 1 and 24 hours, thereaction is allowed to cool to room temperature. Compounds of formula(20) may be filtered and concentrated under reduced pressure. To extractthe compound of formula (20), an organic solvent, such as methylenechloride, may be added, followed by washing with water and brine. Theorganic phase can be concentrated to obtain the compound of formula(20). The compound of formula (20) may be purified by any suitablemethods known in the art such as chromatography on silica gel, reversephase chromatography, trituration, precipitation, or crystallization.

Step 2—Preparation of a Compound of Formula (21)

The compounds of formula (21) may be prepared by reductive amination ofthe compounds of formula (20) by methods known in the art. Compounds offormula (20) and amines, that are commercially available or synthesizedby methods known in the art, can be mixed with a reducing agent such assodium triacetoxy borohydride or sodium cyanoborohydride, in thepresence of an acid, such as acetic acid, or a Lewis acid, such as zincchloride, in a suitable solvent such as dichloroethane or methanol.After stirring at a temperature between 0° C. and room temperature forbetween 1 h and 24 h or until reaction is complete, the reaction may beadded to an aqueous solution, such as saturated aqueous sodiumbicarbonate solution. To extract the compound of formula (21), anorganic solvent, such as ethyl acetate or methylene chloride, may beadded, followed by washing with water and brine. The organic phase canbe concentrated to obtain the compound of formula (21). The compound offormula (21) may be purified by any suitable methods known in the art,such as chromatography on silica gel, trituration, precipitation, orcrystallization.

Reaction Scheme VI

The compounds of formula (22) may be prepared using the alternatemethods similar to the Reaction Scheme VI shown below.

For 27: R^(9a), R^(9b), R^(9c), R^(9d), R^(9e) are as defined herein andwherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), R^(9e) is —COOHFor 22: R^(9a), R^(9b), R^(9c), R^(9d), R^(9e) are as defined herein,and wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), R^(9e) is—CON(R¹⁹)₂

Step 1—Preparation of a Compound of Formula (22)

The compounds of formula (22) can be made by combining the compounds offormula (27) with the commercially available or synthetically preparedamines by methods known in the art. A compound of formula (27) can bemixed with the commercially available or synthetically prepared aminesin the presence of a coupling reagent, such as HATU, and a base, such asdiisopropylethylamine, in a suitable solvent, such as acetonitrile.After stirring at a temperature between room temperature and 100° C. forbetween 1 and 24 hours, the reaction is allowed to cool to roomtemperature. Compounds of formula (22) may be filtered and concentratedunder reduced pressure. To extract the compound of formula (22), anorganic solvent, such as methylene chloride, may be added, followed bywashing with water and brine. The organic phase can be concentrated toobtain the compound of formula (22). The compound of formula (22) may bepurified by any suitable methods known in the art, such aschromatography on silica gel, reverse phase chromatography, trituration,precipitation, or crystallization.

Reaction Scheme VII

The compounds of Formula I may be prepared using the alternate methodssimilar to the Reaction Scheme VII shown below.

Step 1—Preparation of a Compound of Formula (23)

The compounds of formula (23) can be made by borylation of the compoundof formula (9) by methods known in the art. A compound of formula (9)can be mixed with reagents, such as bis(pinacolato)diboron, in thepresence of a base, such as potassium acetate, and a catalyst, such as[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane, in a suitable solvent, such as dioxane. After stirringat a temperature between room temperature and 100° C. for between 1 hand 24 h or until reaction is complete, the compound of formula (23) maybe obtained by any suitable methods known in the art such astrituration, precipitation, or crystallization.

Step 2—Preparation of a Compound of Formula (25)

The compounds of formula (25) can be made by combining compounds offormulas (24) and (11) by methods known in the art. Compounds offormulas (24) and (11) are commercially available or can be made bymethods known in the art. Compounds of formulas (24) and (11) can bemixed in the presence of a base, such as potassium carbonate, in asuitable solvent, such as DMF. After stirring at a temperature betweenroom temperature and 50° C. for between 1 h and 24 h or until reactionis complete, the reaction is cooled to room temperature. To extract thecompound of formula (25), an organic solvent, such as ethyl acetate, maybe added, followed by washing with water and brine. The organic phasecan be concentrated to obtain the compound of formula (25). The compoundof formula (25) may be purified by any suitable methods known in theart, such as chromatography on silica gel, trituration, precipitation,or crystallization.

Step 3—Preparation of a Compound of Formula (26)

The compounds of formula (26) may be prepared by reductive amination ofthe compounds of formula (25) by methods known in the art. Compounds offormula (25) and amines, that are commercially available or synthesizedby methods known in the art, can be mixed with a reducing agent, such assodium triacetoxy borohydride or sodium cyanoborohydride, in thepresence of an acid, such as acetic acid, or a Lewis acid, such as zincchloride, in a suitable solvent, such as dichloroethane or methanol.After stirring at a temperature between 0° C. and room temperature forbetween 1 h and 24 h or until reaction is complete, the reaction may beadded to aqueous solution, such as saturated aqueous sodium bicarbonatesolution. To extract the compound of formula (26), an organic solvent,such as ethyl acetate or methylene chloride, may be added, followed bywashing with water and brine. The organic phase can be concentrated toobtain the compound of formula (26). The compound of formula (26) may bepurified by any suitable methods known in the art, such aschromatography on silica gel, trituration, precipitation, orcrystallization.

Step 4—Preparation of a Compound of Formula I

The compounds of Formula I can be made by combining the compounds offormulas (26) and (23) by methods known in the art. Compounds offormulas (26) and (23) can be mixed in the presence of a catalyst, suchas tetrakis(triphenylphosphine)palladium, and a base, such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic, in asuitable solvent, such as a mixture of dimethoxyethane and water, or amixture of DMAc and water. After stirring at a temperature between 50°C. and 150° C. for between 1 and 24 hours, the reaction is allowed tocool to room temperature. Compounds of Formula I may be filtered andconcentrated under reduced pressure. To extract the compound of FormulaI, an organic solvent such as methylene chloride may be added, followedby washing with water and brine. The organic phase can be concentratedto obtain the compound of Formula I. The compound of Formula I may bepurified by any suitable methods known in the art such as chromatographyon silica gel, reverse phase chromatography, trituration, precipitation,or crystallization.

Reaction Scheme VIII

The compounds of Formula I may be prepared using the alternate methodssimilar to the Reaction Scheme VIII shown below.

Reaction Scheme IX

The compounds of Formula I may be prepared using the alternate methodssimilar to the Reaction Scheme IX shown below.

Reaction Scheme X

The compounds of Formula I may be prepared using the alternate methodssimilar to the Reaction Scheme X shown below.

VIII. Examples

Exemplary chemical entities of the present disclosure are provided inthe specific examples that follow. Those skilled in the art willrecognize that, to obtain the various compounds herein, startingmaterials may be suitably selected so that the ultimately desiredsubstituents will be carried through the reaction scheme with or withoutprotection as appropriate to yield the desired product. Alternatively,it may be necessary or desirable to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent. Furthermore, one of skill in the art will recognize thatthe transformations shown in the schemes below may be performed in anyorder that is compatible with the functionality of the particularpendant groups.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

Procedure 1: Preparation of the Compounds of Formula (6) According toReaction Scheme I

A. Preparation of 2-bromo-5-(isopropylamino)-4-nitropyridine 1-oxide

In a multi-necked, round bottomed flask was placed2-bromo-5-fluoro-4-nitropyridine 1-oxide (1500.0 g, 6.3 mol) in THF (1.5L) and cooled to 0° C. To this was added isopropyl amine (600.0 mL, 7.0mol) drop wise at 0° C. over a period of 30 min. Reaction mixture wasslowly warmed to room temperature and stirred for 24 h. Then, thereaction mixture was filtered, washed with THF to give2-bromo-5-(isopropylamino)-4-nitropyridine 1-oxide which was used in thenext step without further purification.

B. Preparation of 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine

In toluene (21 L) was placed 2-bromo-5-(isopropylamino)-4-nitropyridine1-oxide (1400.0 g, 5.1 mol). To this was added triethylamine (4.2 L)slowly dropwise at room temperature over a period of 30 min and stirredfor 10 min. Then the reaction mixture was cooled to 0° C. followed bythe dropwise addition of POCl₃ (1.4 L) over a period of 30 min. Reactionmixture was slowly warmed to room temperature and heated to 65° C. for 4h. Then, it was cooled to room temperature, poured into ice water andextracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃ solution, followed by brine solution, dried over sodiumsulfate and concentrated under reduced pressure. The crude mixture waspurified by column chromatography using 100-200 mesh silica gel and thecolumn was gradually eluted with 10% ethyl acetate in petroleum ether togive 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine.

C. Preparation of 6-bromo-2-chloro-N3-isopropylpyridine-3,4-diamine

To a solution of 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine(1000.0 g, 3.4 mol) in THF/MeOH (20 L/20 L) was added Zinc dust (1775.0g, 27.2 mol) followed by the dropwise addition of a solution of NH₄Cl(1816.0 g, 34.0 mol) in water (20 L) at room temperature and theresulting reaction mixture was stirred at room temperature for 1 h.Then, the reaction mixture was diluted with ethyl acetate and filteredthrough celite bed. The filtrate was extracted with ethyl acetate andthe organic layer was dried with anhydrous sodium sulfate andconcentrated under reduced pressure. The crude compound was purified bywashing with methyl t-butyl ether to afford6-bromo-2-chloro-N3-isopropylpyridine-3,4-diamine.

D. Preparation of 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine

To a solution of 6-bromo-2-chloro-N3-isopropylpyridine-3,4-diamine(800.0 g, 3.0 mol) in CH(OCH₃)₃ (5.2 L) was added HCOOH (65 mL). Afterthe reaction mixture was stirred at 70° C. for 3 h, the remainingsolvent was removed via distillation. Then water was added and theresulting mixture was extracted with CH₂Cl₂. The combined organic layerswere dried over anhydrous Na₂SO₄, concentrated, and purified by washingwith methyl t-butyl ether to give6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyri dine.

The following compounds were prepared using a similar procedure exceptcommercially available amines including, ethylamine, cyclo-propylamine,and (S)-butylamine, were used instead of isopropylamine:

-   6-bromo-4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridine

-   6-bromo-4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridine

-   (S)-6-bromo-3-(sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridine

Procedure 2: Preparation of the Compounds of Formula (7) According toReaction Scheme I

A. Preparation of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine

A mixture of 6-bromo-3-isopropyl-4-chloro-3H-imidazo[4,5-c]pyridine (148g, 0.54 mol) and cesium fluoride (819 g, 5.40 mol) in DMF (1.2 L) washeated at 110° C. for 24 h. Reaction mixture was poured into ice water(1 L). The aqueous layer was extracted with ethyl acetate (3×1 L). Theorganic layers were dried over sodium sulfate and concentrated and thecrude mixture was further purified using column chromatography(EA/Hex=2:3-1:1) to yield6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 1 were used instead of6-bromo-3-isopropyl-4-chloro-3H-imidazo[4,5-c]pyridine:

-   6-bromo-3-ethyl-4-fluoro-3H-imidazo[4,5-c]pyridine

-   6-bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine

-   (S)-6-bromo-3-(sec-butyl)-4-fluoro-3H-imidazo[4,5-c]pyridine

Procedure 3: Preparation of the Compounds of Formula (9) According toReaction Scheme I

A. Preparation of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

In a microwave vial were placed6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (200 mg, 0.77mmol), 5-amino-N,2-dimethylbenzamide (381.74 mg, 2.32 mmol), andPyridine.HCl (268.65 mg, 2.32 mmol) in IPA (4 ml). The mixture wasplaced in the microwave reactor and heated at 150° C. for 6 h. Withoutwork-up, the reaction mixture was purified by flash chromatography (100%Hexane to 100% EtOAc followed by 100% DCM to 25% MeOH in DCM). Thefractions were collected and concentrated. The resulting residue wasredissolved in EtOAc and water, and extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried (Na₂SO₄), andconcentrated. To this residue was added DME and the suspension wasfiltered to give5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed in Procedure 1 or 2 were used instead of        6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine; and/or    -   the optionally substituted amino benzamide indicated below were        used instead of 5-amino-N,2-dimethylbenzamide:

-   5-((6-Bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-Amino-2-methylbenzamide was used to prepare    5-((6-Bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide

-   (S)-5-((6-Bromo-3-(sec-butyl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((6-Bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-Amino-2-chloro-N-methylbenzamide was used to prepare    5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-methylbenzamide

-   5-Amino-2-chloro-N-methylbenzamide was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-methylbenzamide

Procedure 4: Preparation of the Compounds of Formula (9) According toReaction Scheme I

A. Preparation of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid

To a solution of 5-amino-4-fluoro-2-methylbenzoic acid (2.0 g, 18 mmol)in DMF (40 mL) was added sodium hydride (1.4 g, 36 mmol) over a periodof 5 minutes. The mixture was stirred at room temperature for 15 minutesfollowed by the addition of6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (5.5 g, 21 mmol).After stirring at room temperature for 16 hours, the reaction mixturewas quenched with water (200 mL). The slurry was stirred for 1 hour,filtered, and washed with water to give6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   5-amino-2-methylbenzoic acid was used instead of        5-amino-4-fluoro-2-methylbenzoic acid; and/or    -   6-bromo-3-ethyl-4-fluoro-3H-imidazo[4,5-c]pyridine was used        instead of        6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine; and/or    -   5-amino-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide        was used instead of 5-amino-4-fluoro-2-methylbenzoic acid:

-   5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic    acid

-   5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic    acid

-   5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide

Procedure 5: Preparation of the Compounds of Formula (19) According toReaction Scheme V A. Preparation of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N,2-dimethylbenzamide

In a vial were placed5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid (1.00 g, 2.46 mmol), HATU (1.12 g, 2.95 mmol, 1.2 eq), MeCN (12mL), DIPEA (4.28 mL, 24.6 mmol, 10.0 eq), and methylamine (4.9 mL, 9.8mmol, 4.0 eq, 2.0 M in THF). The vial was sealed and the resultingmixture was heated at 40° C. for 2 h. Then the reaction was quenchedwith sat. NaHCO₃ and extracted with DCM. The combined organic layerswere washed with 1M K₂CO₃, dried over Na₂SO₄, filtered, concentrated,and purified by flash chromatography (100% DCM to 100% MeOH) to give5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the amines indicated below were used instead of methylamine;        and/or    -   the compounds listed under Procedure 4 were used instead of        5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic        acid:

-   2,2-Difluoroethan-1-amine was used instead of methylamine to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-2-methylbenzamide

-   1,1-Difluoropropan-2-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1,1-difluoropropan-2-yl)-2-methylbenzamide

-   1-(Difluoromethyl)cyclobutan-1-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclobutyl)-2-methylbenzamide

-   1-(Difluoromethyl)cyclopropan-1-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-2-methylbenzamide

-   1,3-Difluoropropan-2-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1,3-difluoropropan-2-yl)-2-methylbenzamide

-   (S)-1-Fluoropropan-2-amine was used to prepare    (S)-5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-fluoropropan-2-yl)-2-methylbenzamide

-   (R)-1-Fluoropropan-2-amine was used to prepare    (R)-5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-fluoropropan-2-yl)-2-methylbenzamide

-   Ethylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2-methylbenzamide

-   iso-Propylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide

-   Cyclobutanamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-cyclobutyl-2-methylbenzamide

-   Cyclopropylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-cyclopropyl-2-methylbenzamide

-   n-Propylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methyl-N-propylbenzamide

-   3,3-Difluoropropan-1-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(3,3-difluoropropyl)-2-methylbenzamide

-   2,2-Difluoropropan-1-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoropropyl)-2-methylbenzamide

-   Ethylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamide

-   iso-Propylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide

-   1-(Difluoromethyl)cyclopropan-1-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide

-   iso-Propylamine was used to prepare    5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide

-   Ethylamine was used to prepare    5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-ethyl-2-methylbenzamide

-   tert-Butylamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(tert-butyl)-4-fluoro-2-methylbenzamide

-   Cyclobutanamine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-cyclobutyl-4-fluoro-2-methylbenzamide

-   2-Methylpropan-1-amine was used to prepare    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-isobutyl-2-methylbenzamide

Procedure 6: Preparation of the Compounds of Formula (13) According toReaction Scheme I

A. Preparation of3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

A mixture of 6-bromo-3,3-dimethylindolin-2-one (150 g, 625 mmol),bis(pinacolato)diboron (206 g, 812 mmol), Pd(dppf)Cl₂/CH₂Cl₂ (45 g, 62.5mmol) and potassium acetate (184 g, 1875 mmol) in dimethyl sulfoxide(2000 mL) was stirred at 100° C. under Ar for 3 h. The reaction wasdiluted with H₂O (10 L) and extracted with ethyl acetate (4 L). Theorganic phase was washed with water followed by brine, dried overNa₂SO₄, and purified by silica gel column (PE/EA=10:1) to give3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

B. Preparation of3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a mixture of3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(200 g, 696 mmol) and K₂CO₃ (240 g, 1740 mmol) in DMF (2 L) was added3-bromocyclobutanone (160 g, 1356 mmol). After the mixture was stirredat 50° C. under Ar for 2.5 h, it was cooled to room temperature, dilutedwith EtOAc, and filtered to remove solids. The filtrate was diluted withadditional EtOAc and water. The aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated, and purified by flash chromatography on silicagel (PE/EA=20:1) to give3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

The following compounds were prepared using a similar procedure except:

-   Commercially available 6-bromo-3,3-difluoroindolin-2-one was used    instead of    3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one    to prepare 6-bromo-3,3-difluoro-1-(3-oxocyclobutyl)indolin-2-one

-   6-bromo-3,3-diethylindolin-2-one (Prepared According to the    Procedure Described in Paragraph [1008] of WO2009078481) was used    instead of    3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one    to prepare 6-bromo-3,3-diethyl-1-(3-oxocyclobutyl)indolin-2-one

-   Commercially available 6-bromo-3,3-dimethylindolin-2-one was used    instead of    3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one    to prepare 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one

C. Preparation of3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a solution of3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(7.0 g, 19.7 mmol) in dichloroethane (130 mL) was added piperidine (3.4g, 39.4 mmol) and acetic acid (3.6 g, 59.1 mmol). The reaction wascooled to 0° C. in an ice-bath and sodium triacetoxy borohydride (6.26g, 29.56 mmol) was added portion-wise. After completion of addition, thereaction was brought out of the ice bath and stirred at room temperaturefor 2 h. Then, the reaction mixture was quenched with saturated aqueoussodium bicarbonate solution and extracted with methylene chloride (3×200mL). The combined organic layers were washed with sat. NaHCO₃, brine,dried over sodium sulfate, filtered, and concentrated in vacuo to give3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the amines indicated below were used instead of piperidine; or    -   the optionally substituted oxindoles, that are commercially        available or can be made by methods known in the art, such as        6-bromo-3,3-difluoro-1-(3-oxocyclobutyl)indolin-2-one and        6-bromo-3,3-diethyl-1-(3-oxocyclobutyl)indolin-2-one, were used        instead of        3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one:

-   3,3-Dimethylpyrrolidine was used to prepare    1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (R)-3-Fluoropyrrolidine was used to prepare 1-((1    S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (S)-3-Fluoropyrrolidine was used to prepare 1-((1R,3    s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   3-Oxa-6-azabicyclo[3.1.1]heptane was used to prepare    1-((1s,3s)-3-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (1R,4S)-2-Azabicyclo[2.2.1]heptane was used to prepare 1-((1    S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   3-Oxa-8-azabicyclo[3.2.1]octane was used to prepare    1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   8-Oxa-3-azabicyclo[3.2.1]octane was used to prepare    1-((1s,3s)-3-(8-oxa-3-azabicyclo[30.2.1]octan-3-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   6,6-Difluoro-3-azabicyclo[3.1.0]hexane was used to prepare    1-((1s,3s)-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   2-Fluoro-2-methylpropan-1-amine was used to prepare    1-((1s,3s)-3-((2-fluoro-2-methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   3,3-dimethylpiperidine was used to prepare    1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (S)-Piperidin-3-ol was used to prepare    1-((1R,3s)-3-((S)-3-hydroxypiperidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (R)-Piperidin-3-ol was used to prepare    1-((1S,3s)-3-((R)-3-hydroxypiperidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   2,2-Dimethylmorpholine was used to prepare 1-((1    s,3s)-3-(2,2-dimethylmorpholino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   Morpholine was used to prepare    3,3-dimethyl-1-((s,3s)-3-morpholinocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (R)-3-Fluoropiperidine was used to prepare 1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   3,3-Dimethylazetidine was used to prepare    1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   1-Amino-2-methylpropan-2-ol was used to prepare    1-((1s,3s)-3-((2-hydroxy-2-methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   i-Propylamine was used to prepare    1-((1s,3s)-3-(isopropylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (3R,4R)-3-Methyltetrahydro-2H-pyran-4-amine was used to prepare    3,3-dimethyl-1-((1 S,3    s)-3-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   (3 S,4R)-3-Methyltetrahydro-2H-pyran-4-amine was used to prepare    3,3-dimethyl-1-((1 S,3 s)-3-(((3    S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   4,4-Difluorocyclohexan-1-amine was used to prepare    1-((1s,3s)-3-((4,4-difluorocyclohexyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   3,3-Difluorocyclobutan-1-amine was used to prepare    1-((1s,3s)-3-((3,3-difluorocyclobutyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

-   6-Bromo-3,3-difluoro-1-(3-oxocyclobutyl)indolin-2-one was used    instead of    3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one    to prepare    6-bromo-3,3-difluoro-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

-   6-Bromo-3,3-diethyl-1-(3-oxocyclobutyl)indolin-2-one was used    instead of    3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one    to prepare    6-bromo-3,3-diethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

Procedure 7: Preparation of the Compounds of Formula (13) According toReaction Scheme I

A. Preparation of3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

To a stirring solution of6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4 g,16.59 mmol) in dioxane (100 ml) were added bis(pinacolato)diboron (12.64g, 49.77 mmol), potassium acetate (4.88 g, 49.77 mmol), andPd(dppf)Cl₂/DCM (1354.92 mg, 1.66 mmol). The reaction mixture wasdegassed with N₂ for 5 min, sealed, and heated at 100° C. for 15 h. Thereaction mixture was cooled to room temperature, and then filteredthrough a pad of celite. The filtrate was diluted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andthen concentrated to give3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewhich was used in the next step without further purification.

The following compound was prepared using a similar procedure except6-bromo-3,3-diethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-onewas used instead6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one:

-   3,3-Diethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

B. Preparation of(3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid

To a stirring solution3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one(1.1 g, 3.82 mmol) in NMP (20 ml) were added 3-bromocyclobutanone(1354.15 μl, 15.27 mmol) and K₂CO₃ (2.64 g, 19.09 mmol). The resultingmixture was heated at 50° C. for 15 h. The reaction mixture was cooledto room temperature and then diluted with EtOAc. The organic layer waswashed with water followed by brine, dried over Na₂SO₄, filtered, thenconcentrated to give(3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid, which was used in the next step without further purification.

C. Preparation of(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid

To a stirring solution of(3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid (2 g, 5.61 mmol) in DCE (30 ml) were added piperidine (1.11 ml,11.2 mmol), Na(OAc)₃BH (1.78 g, 8.42 mmol), and AcOH (0.97 ml, 16.8mmol) at room temperature. The resulting mixture was stirred for 2 hthen quenched with satd. NaHCO₃. Aqueous layer was extracted with DCMand the combined organic layer was dried over Na₂SO₄, then concentratedto give(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid, which was used in the next step without further purification.

The following compound was prepared using a similar procedure except theamine indicated below was used instead of piperidine:

-   (1R,4S)-2-azabicyclo[2.2.1]heptane was used instead of piperidine to    Prepare (1-((1 S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronic    acid

Procedure 8: Preparation of the Compounds of Formula (13) According toReaction Scheme I

A. Preparation of3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

To a stirring solution of 6-bromo-3-hydroxy-3-methylindolin-2-one (4 g,16.5 mmol) in dioxane (80 ml) were added bis(pinacolato)diboron (8.4 g,33 mmol), potassium acetate (3.2 g, 33 mmol), and Pd(dppf)Cl₂-DCM (1.4g, 1.65 mmol). The nitrogen gas was bubbled through the resultingsuspension for 3 min then heated over night at 90° C. After cooling toroom temperature, the reaction mixture was filtered and the filter cakewas washed with EtOAc then concentrated in vacuo. The crude product waspurified by silica gel chromatography (Hexanes/EtOAc) to afford3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

B. Preparation of3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a stirring solution of3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onein NMP (100 mL) were added 3-bromocyclobutanone (5.53 ml, 62.4 mmol) andpotassium carbonate (325 mesh, 10.8 g, 78 mmol). The resultingsuspension was stirred at 50° C. for overnight. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (100 ml) andthe organic layer was washed with water (100 ml), brine (100 ml), driedover Na₂SO₄, concentrated, and purified by flash chromatography(Hexanes/EtOAc) to afford3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

C. Preparation of3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a solution of3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(3.0 g, 8.4 mmol) in dichloroethane (60 mL) was added piperidine (1.4 g,16.8 mmol), acetic acid (1.5 mL, 25.2 mmol), and sodium triacetoxyborohydride (2.7 g, 12.6 mmol). After stirring at room temperature for 5h, the reaction mixture was quenched with saturated aqueous sodiumbicarbonate solution and extracted with methylene chloride (3×200 mL).The combined organic layers were washed with sat. NaHCO₃, brine, driedover sodium sulfate, filtered, and concentrated in vacuo to give3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one,which was used in the next step without purification.

Procedure 9: Preparation of the Compounds of Formula (17) Shown inReaction Schemes I and IV

A. Preparation of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a mixture of tert-butyl2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(0.81 g, 1.89 mmol), which can be prepared following the literatureprocedure (intermediate 7.33 in WO2015017610 A1, also published as), andpowdered potassium carbonate (0.65 g of 325 mesh, 4.73 mmol) in DMF (7.5mL) was added 3-bromocyclobutanone (0.21 mL, 2.53 mmol). After themixture was heated to 50° C. for 1 h, it was cooled to room temperatureand filtered to remove potassium carbonate. The filtrate was dilutedwith EtOAc and water, and extracted with EtOAc. The combined organiclayers were washed with brine, dried (Na₂SO₄), filtered, concentrated,and purified via flash chromatography on silica gel with gradientelution (0-100% EtOAc/hexanes) to give tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a mixture of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(0.5 g, 1.0 mmol) in DCE (10 mL) was added piperidine (0.3 mL, 3.0mmol), AcOH (0.2 mL, 3.0 mmol), and sodium triacetoxyborohydride (320mg, 1.5 mmol). After stirring at room temperature for 16 h, the reactionmixture was diluted with sat. NaHCO₃ and DCM and stirred vigorously for5 min. The organic layer was separated, dried over Na₂SO₄, andconcentrated under reduced pressure to give tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

The following compounds were prepared using a similar procedure exceptthe amines indicated below were used instead of piperidine:

-   3,3-Dimethylpyrrolidine was used to prepare tert-butyl    1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   1,1-Difluoro-5-azaspiro[2.4]heptane was used to prepare tert-butyl    1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   3,3-Dimethylpiperidine was used to prepare tert-butyl    1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   3,3,5,5-Tetramethylpiperidine was used to prepare tert-butyl    2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((1s,3s)-3-(3,3,5,5-tetramethylpiperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   5-Azaspiro[2.5]octane was used to prepare tert-butyl    1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   1,1-Difluoro-5-azaspiro[2.5]octane was used to prepare tert-butyl    1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   (1R,4S)-2-azabicyclo[2.2.1]heptane was used to prepare tert-butyl    1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   3-Oxa-8-azabicyclo[3.2.1]octane was used to prepare tert-butyl    1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   8-Oxa-3-azabicyclo[3.2.1]octane was used to prepare tert-butyl    1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   (R)-3-fluoropyrrolidine was used to prepare tert-butyl 1-((1    S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   (S)-3-Fluoropyrrolidine was used to prepare tert-butyl 1-((1R,3    s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   6,6-Difluoro-3-azabicyclo[3.1.0]hexane was used to prepare    tert-butyl    1-((1s,3s)-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

C. Preparation of tert-butyl1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(250 mg, 0.5 mmol) in MeOH (6 mL) was added (R)-3-fluoropiperidinehydrochloride (211 mg, 1.5 mmol), zinc chloride (103 mg, 0.76 mmol), andsodium cyanoborohydride (95 mg, 1.5 mmol). After stirring overnight atroom temperature, the reaction was diluted with sat. NaHCO₃ and DCM andstirred vigorously for five minutes. Then the organic layer wasseparated, dried (Na₂SO₄), and concentrated to give tert-butyl 1-((1 S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

Procedure 10: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a solution of tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(2.27 g, 4.01 mmol) in dioxane (20 mL) was added 4M hydrochloric acidsolution (19.07 ml). The mixture was stirred at room temperature for 10min, at which point LC-MS indicated complete conversion. The mixture wasconcentrated and the trace amounts of acid were chased off on therotovap using methanol three times. The residue was dissolved in minimalDCM, and then crashed out with ether and hexanes. The precipitates werefiltered and washed with hexanes to provide1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 9 were used instead of tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate:

-   1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1    s,3s)-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1    S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1R,3    s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxabrolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1 S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

Procedure 11: Preparation of the Compounds of Formula (13) According toReaction Scheme I

A. Preparation of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

To a stirring solution of6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one (4 g,16.5 mmol) in DMSO (1160 ml) were added bis(pinacolato)diboron (20.1 g,24.7 mmol), potassium acetate (80.7 g, 822 mmol), and Pd(dppf)Cl₂ (20.1g, 24.7 mmol). The nitrogen gas was bubbled through the resultingsuspension for 5 min and then the suspension was heated at 90° C. for 6h. After cooling to room temperature, the reaction mixture was dilutedwith EtOAc and washed with brine. The organic layer was dried (Na₂SO₄),filtered, concentrated, triturated with petroleum ether/EtOAc, andfiltered to give6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one.

B. Preparation of1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

To a stirring solution of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one(67.0 g, 203 mmol) in DMF (500 mL) was added potassium carbonate (70.3g, 509 mmol). After stirring at 50° C. for 4 h, 3-bromocyclobutanone(60.6 g, 407 mmol) was added to the mixture. The resulting suspensionwas stirred at 50° C. for 1 h. After cooling to room temperature, thereaction mixture was filtered, concentrated, and purified by flashchromatography (Petroleum ether/EtOAc) to afford1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one.

C. Preparation of1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

To a solution of1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one(3.0 g, 8.4 mmol) in dichloroethane (30 mL) was added3,3-dimethylpyrrolidine (1.5 g, 15.1 mmol), acetic acid (1.4 mL, 22.7mmol), and sodium triacetoxy borohydride (2.4 g, 11.3 mmol). Afterstirring at room temperature for 48 h, the reaction mixture was quenchedwith saturated aqueous sodium bicarbonate solution and extracted withmethylene chloride. The combined organic layers were washed with sat.NaHCO₃, brine, dried over sodium sulfate, filtered, and concentrated invacuo to give1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one,which was used in the next step without purification.

The following compound was prepared using a similar procedure exceptpiperidine was used instead of 3,3-dimethylpyrrolidine:

-   1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

Procedure 12: Preparation of the Compounds of Formula (I-B) According toReaction Scheme IV

A. Preparation of1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(1810 mg, 3.89 mmol) and triethylamine (5.42 ml, 38.89 mmol) indichloromethane (8 ml) was added acetic anhydride (0.55 ml, 5.83 mmol).The mixture was stirred at room temperature for 1 h, then diluted withDCM and water, and extracted with DCM. The combined organic layers werewashed with brine and concentrated to provide1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 10 were used instead of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

-   1′-Acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-1′-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-1′-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1 S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-1′-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

B. Preparation of1′-(2-hydroxy-2-methylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

In a 20 mL vial were placed1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(200.0 mg, 0.4 mmol), 2-hydroxy-2-methylpropanoic acid (103.7 mg, 1.0mmol), HATU (364.6 mg, 1.0 mmol), and N,N-Diisopropylethylamine (0.7 ml,4.0 mmol) in ACN (9 ml). The mixture was stirred at room temperature for16 h. Then the mixture was quenched with saturated NaHCO₃ and extractedwith DCM. The combined organic layers were washed with water and brine,dried (Na₂SO₄), concentrated, and used in the next step withoutpurification.

The following compounds were prepared using a similar procedure exceptthe carboxylic acids indicated below were used instead of2-hydroxy-2-methylpropanoic acid:

-   (R)-2-Hydroxypropanoic acid was used to prepare    1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   Propionic acid was used to prepare    1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1′-propionyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

C. Preparation of1′-(1-methylcyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(0.3 g, 0.6 mmol) in DMF (3 mL) was added1-methylcyclopropane-1-carboxylic acid (0.12 g, 1.2 mmol), DIEA (1.04mL, 5.97 mmol) followed by a 50% solution of propylphosphonic anhydride(T3P) in EtOAc, (0.31 mL, 0.53 mmol) and the mixture was stirred at roomtemperature for 72 h. The mixture was then quenched with water andextracted twice with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), concentrated to give1′-(1-methylcyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the carboxylic acids indicated below were used instead of        1-methylcyclopropane-1-carboxylic acid; and/or    -   the compounds listed under Procedure 10 were used instead of        1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

-   3-Fluorobicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare    1′-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   Bicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare    1′-(bicyclo[1.1.1]pentane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   Oxetane-3-carboxylic acid was used to prepare 1-((1 S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-1′-(oxetane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   Bicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare 1-((1    S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-1′-(bicyclo[1.1.1]pentane-1-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

D. Preparation of methyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(0.3 g, 0.6 mmol) in DCM (5 mL) was added DIEA (1.0 mL, 5.6 mmol) andmethyl carbonochloridate (0.1 g, 1.1 mmol). After the mixture wasstirred at room temperature for 2 h, it was quenched with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), and concentrated to give methyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylatewhich was used in the next step without purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the carboxylic acid chloride indicated below was used instead of        methyl carbonochloridate; and/or    -   the compounds listed under Procedure 10 were used instead of        1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

-   Cyclopropanecarbonyl chloride was used to prepare    1′-(cyclopropanecarbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   Isobutyryl chloride was used to prepare    1′-isobutyryl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   Propionyl chloride was used to prepare    1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1′-propionyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

E. Preparation of1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(1.50 g, 2.79 mmol) and 3-oxetanone (0.49 mL, 0.60 g, 8.4 mmol) inmethanol (28 mL) was added zinc chloride (570 mg, 4.18 mmol), followedby sodium cyanoborohydride (525 mg, 8.36 mmol). The mixture was sealedand heated to 40° C. with stirring for 2 h. The reaction mixture wascooled, saturated aqueous sodium bicarbonate was added, and the aqueouslayer was extracted three times with ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated undervacuum. The resulting residue was dissolved in EtOAc, washed once morewith saturated aqueous sodium bicarbonate, dried over sodium sulfate,filtered, and concentrated under vacuum to afford1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 10 were used instead of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

-   1-((1s,3s)-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1 S,3    s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1R,3    s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

-   1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

F. Preparation of1′-(2,2-difluoroethyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

The mixture of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(1.00 g, 1.86 mmol), 1,1-difluoro-2-iodoethane (196 μL, 2.23 mmol), andpotassium carbonate (1.03 g, 7.43 mmol) in DMF (1.3 mL) was placed in asealed tube and stirred at 70° C. overnight. After stirring overnight,the reaction was quenched with saturated aqueous sodium bicarbonate andextracted with DCM. The combined organic layers were washed with water,dried over sodium sulfate, filtered, and concentrated to provide1′-(2,2-difluoroethyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

Procedure 13: Preparation of the Compounds of Formula I According toReaction Scheme I

A. Preparation of5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 1)

In a microwave vial were placed5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(50 mg, 0.12 mmol),3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(52.75 mg, 0.12 mmol), Pd(PPh₃)₄ (10.05 mg, 0.01 mmol), and cesiumcarbonate (80.99 mg, 0.25 mmol) in DME (2 ml)/H2O (1 ml). The mixturewas placed in the microwave reactor and heated at 125° C. for 25 min.Then the mixture was purified by flash chromatography (100% DCM to 50%MeOH in DCM) and reverse phase chromatography to give5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 3, 4, or 5 were used        instead of        5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide;        and/or    -   the compounds listed under Procedure 6, 7, 8, 9, 11, 12, 34, or        35 were used instead of        3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one:

Structure Example #

 2

 3

 4

 5

 6

 7

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 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

 58a A mixture of dioxane and water was used as a solvent instead of amixture of DME and water to prepare this compound

59 Na₂CO₃ was used as a base instead of Cs₂CO₃ to prepare this compound

60 Na₂CO₃ was used as a base instead of Cs₂CO₃ to prepare this compound

61 Na₂CO₃ was used as a base instead of Cs₂CO₃ to prepare this compound

62 Na₂CO₃ was used as a base instead of Cs₂CO₃ to prepare this compound

63 Na₂CO₃ was used as a base instead of Cs₂CO₃ to prepare this compound

64 Na₂CO₃ was used as a base instead of Cs₂CO₃ to prepare this compound

65

66

67

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamideto prepare5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid.

B. Preparation of2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide(Example 244)

2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

C. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one(Example 68)

In a scintillation vial were placed1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(78 mg, 0.15 mmol),5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N,2-dimethylbenzamide(82 mg, 0.195 mmol, 1.3 eq), Pd(PPh₃)₄ (17 mg, 0.015 mmol, 0.1 eq), inDME (0.6 mL), and Na₂CO₃ (0.3 mL, 0.6 mmol, 4.0 eq, 2.0 M in water). Themixture was flushed with nitrogen and sealed, and was stirred overnightat 100° C. Then, the mixture was allowed to cool to room temperature andquenched with 1 M K₂CO₃. The mixture was extracted with DCM/MeOH,filtered through celite, and concentrated. The crude material waspurified on combiflash (12 g gold column, DCM to 15% MeOH in DCM to 50%to 100% MeOH), then reverse-phase HPLC was performed to afford6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 3, 4, or 5 were used        instead of        5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N,2-dimethylbenzamide    -   the compounds listed under Procedure 6 or 12 were used instead        of        1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

Structure Example #

69

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72

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75

76

77

78

79

80 A mixture of DMAc and water was used as a solvent and K₃PO₄ as a baseinstead of a mixture of DME and water and Na₂CO₃, respectively, toprepare this compound

81 A mixture of DMAc and water was used as a solvent and K₃PO₄ as a baseinstead of a mixture of DME and water and Na₂CO₃, respectively, toprepare this compound

82 A mixture of DMAc and water was used as a solvent and K₃PO₄ as a baseinstead of a mixture of DME and water and Na₂CO₃, respectively, toprepare this compound

Procedure 14: Preparation of the Compounds of Formula (14) According toReaction Scheme

A. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

To a solution of3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(1.0 g, 0.305 mmol) in DME (100 ml) were added6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (0.97 g, 3.53mmol), Pd(PPh₃)₄ (55 mg, 0.047 mmol), and 2M Na₂CO₃ (1.77 ml, 3.53mmol). The resulting mixture was degassed by bubbling argon gas throughfor 3 min and then the reaction vessel was sealed. After heating at 90°C. for 1 h, the reaction mixture was cooled then diluted with EtOAc. Theorganic layer was washed with water, brine, dried over Na₂SO₄,concentrated, and purified by flash chromatography (DCM/MeOH 50%) toafford6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine; and/or    -   the compounds listed under Procedure 6, 7, 9, 11, or 36 were        used instead of        3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one;        and/or    -   Cs₂CO₃ was used as a base for the compounds indicated below:

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl--((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

-   6-(4-Chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   2M Cs₂CO₃ was used as a base instead of 2M Na₂CO₃ to prepare    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

-   2M Cs₂CO₃ was used as a base instead of 2M Na₂CO₃ to prepare    6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1    s,3R)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

-   6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3R)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   6-(3-((S)-sec-Butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

-   tert-butyl    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(3,3,5,5-tetramethylpiperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1    s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    s,3R)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   2M Cs₂CO₃ was used as a base instead of 2M Na₂CO₃ to prepare    tert-butyl    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-((R)-3-difluoro-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   N-((1s,3s)-3-(3,3-dimethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)cyclobutyl)pivalamide    (synthesis described in Procedure 36) and    6-bromo-4-chloro-3-ethyl-3H-imidazo[4,5-c]pyri dine were used    instead of    3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one    and 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine,    respectively, to prepare    N-((1s,3s)-3-(6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-2-oxoindolin-1-yl)cyclobutyl)pivalamide

Procedure 15: Preparation of the Compounds of Formula (14) According toReaction Scheme II

A. Preparation of1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

In a round bottomed flask were placed1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(0.8 g, 1.6 mmol),6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (866 mg, 3.2mmol), Pd(PPh₃)₄ (91 mg, 0.08 mmol), and cesium carbonate (668 mg, 6.3mmol). To this mixture were added DME (10 mL) and water (3 mL) and theresulting mixture was heated to 120° C. for 1 h under nitrogenatmosphere. Then it was diluted with EtOAc and water, and extracted withEtOAc. The combined organic layers were concentrated under reducedpressure and purified by column chromatography (0-10% DCM/MeOH) to give1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine; and/or    -   the compounds listed under Procedure 11, 12, or 36 were used        instead of        1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1    s,3    S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   1′-acetyl-6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    s,3)-2-hydroxypropanoyl)-3-(piperidin-((1-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   Na₂CO₃ as a base instead of Cs₂CO₃ was used to prepare    1′-acetyl-6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    s,33R)-3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

-   N-((1s,3s)-3-(6-(4-Chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-2-oxoindolin-1-yl)cyclobutyl)pivalamide

Procedure 16: Preparation of the Compounds of Formula (I-B) According toReaction Schemes II and IV

A. Preparation of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

To a flask was charged tert-butyl1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(1.0 g, 1.7 mmol),6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (0.9 g, 3.4mmol), Pd(PPh₃)₄ (0.2 g, 0.17 mmol), and cesium carbonate (2.0 g, 6.8mmol). DME (10 mL) and water (3 mL) were added and the reaction washeated to 120° C. for 1 h under nitrogen atmosphere. The reaction wasdiluted with EtOAc and water, and extracted with EtOAc. The combinedorganic layers were concentrated under reduced pressure and purified bycolumn chromatography (100% DCM to 10% MeOH/DCM) to give tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate(550 mg, 0.85 mmol) in dichloromethane (5 mL) was added 4N HCl indioxane (1 mL). After stirring at room temperature overnight, thereaction mixture was concentrated under reduced pressure to afford6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under the procedure 14 were used instead oftert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate:

-   6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

C. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetane-3-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

In a flask was placed6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(82 mg, 0.14 mmol), oxetane-3-carboxylic acid (17 mg, 0.17 mmol), andDIPEA (0.70 ml, 0.12 mmol) in DMF (1 mL). To this mixture was added HATU(80 mg, 0.21 mmol). The mixture was stirred at room temperature for 1 h,then quenched with water and extracted with DCM. The combined organiclayers were washed with water and brine, dried (Na₂SO₄), concentrated,and purified by reverse phase HPLC to give6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetane-3-carbonyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure except:

-   -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine; and/or    -   the compounds listed in the Procedure 10 were used instead of        tert-butyl        1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate;        and/or    -   the carboxylic acids indicated below were used instead of        oxetane-3-carboxylic acid:

-   1-Hydroxycyclopropane-1-carboxylic acid was used to prepare    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(1-hydroxycyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   1-Hydroxycyclopropane-1-carboxylic acid was used to prepare    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(1-hydroxycyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   3-Methyloxetane-3-carboxylic acid was used to prepare    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(3-methyloxetane-3-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   3-Methyloxetane-3-carboxylic acid was used to prepare    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(3-methyloxetane-3-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

D. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

To a flask charged with6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(460 mg, 0.84 mmol) and 3-oxetanone (182 mg, 2.5 mmol) in methanol (3mL) was added zinc chloride (172 mg, 1.3 mmol) followed by sodiumcyanoborohydride (159 mg, 2.5 mmol). The mixture was sealed and heatedto 40° C., stirred for 2 h., cooled, and then quenched with saturatedaqueous sodium bicarbonate. The aqueous layer was extracted three timeswith dichloromethane. The combined organic layers were dried over sodiumsulfate, filtered, concentrated under vacuum, and purified by reversephase HPLC to give6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 9 were used instead of        tert-butyl        1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate:

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

-   6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

Procedure 17: Preparation of the Compounds of Formula (22) According toReaction Scheme V

A. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one

To a solution of 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine(2 g, 7.29 mmol) in DME (30 ml) were added Pd(PPh₃)₄ (589 mg, 0.51mmol), 2M Na₂CO₃ (18.2 ml, 36 mmol), and3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(3.1 g, 8.74 mmol). The resulting suspension was degassed by bubbling Argas through (2 min), sealed, then heated to 90° C. for 4 h. The reactionmixture was cooled to room temperature then diluted with EtOAc. Theorganic layer was washed with water, brine, dried over Na₂SO₄,concentrated, and purified by flash chromatography (Hex/EtOAc) to give6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one.

B. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(pyrrolidin-1-yl)cyclobutyl)indolin-2-one

To a stirring solution of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one(200 mg, 0.47 mmol) in DCE (5 ml) were added pyrrolidine (67 mg, 0.95mmol), Na(OAc)₃BH (150 mg, 0.79 mmol), and AcOH (0.081 ml, 1.42 mmol) atroom temperature. The resulting mixture was stirred for 2 h thenquenched with satd. NaHCO₃, and extracted with DCM. The combined organiclayers were dried over Na₂SO₄, then concentrated and purified by flashchromatography (Hexanes/EtOAc) to give6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(pyrrolidin-1-yl)cyclobutyl)indolin-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the amines indicated below were used instead of pyrrolidine;        and/or    -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine:

-   Piperidine was used to prepare    6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

-   3-(Difluoromethyl)pyrrolidine was used to prepare    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3-(difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   3-(Difluoromethyl)piperidine was used to prepare    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3-(difluoromethyl)piperidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   (R)-3-Fluoropyrrolidine was used to prepare    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 S,3    s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   Piperidine was used to prepare    6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

Procedure 18: Preparation of the Compounds of Formula I According toReaction Scheme II

A. Preparation of5-((6-(1′-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide(Example 83)

In a 40 mL microwave reaction vial were placed1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(880 mg, 1.53 mmol), 5-amino-N-isopropyl-2-methylbenzamide (588.33 mg,3.06 mmol), Pd₂(dba)₃ (98.08 mg, 0.11 mmol), Xanthphos (110.25 mg, 0.21mmol), and Cs₂CO₃ (1995.15 mg, 6.12 mmol) in Dioxane (6 ml). The mixturewas sonicated and degassed for 15 sec, placed in the microwave reactor,and heated at 150° C. for 1 h. Then the mixture was purified by flashchromatography (100% DCM to 80% MeOH in DCM) followed by reverse phasechromatography to give5-((6-(1′-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 14, 15, 16, 17, or 37 were        used instead of        1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one;        and/or    -   the optionally substituted benzamides, that are commercially        available, such as 5-amino-N,2-dimethylbenzamide,        5-amino-4-fluoro-N,2-dimethylbenzamide,        5-amino-2-chloro-N-methylbenzamide, and        5-amino-2-chloro-N-isopropylbenzamide, or can be made by methods        known in the art, such as the compounds listed under Procedure        27 were used instead of 5-amino-N-isopropyl-2-methylbenzamide:

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-   Methyl 5-amino-2-methylbenzoate and    6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1    s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one were used instead    of 5-amino-N-isopropyl-2-methylbenzamide and    1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one,    respectively, to prepare methyl    5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate

B. Preparation of tert-butyl6-(3-isopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(0.7 g, 1.1 mmol) in dioxane (9 ml) were added5-amino-N,2-dimethylbenzamide (0.91 g, 5.5 mmol), Pd₂(dba)₃ (0.11 g,0.11 mmol), Xanthphos (0.13 g, 0.22 mmol), and Cs₂CO₃ (1.8 g, 5.5 mmol).The resulting mixture was degassed by bubbling nitrogen gas through fora few minutes and then the reaction vessel was sealed. After heating for30 minutes at 150° C. in the microwave, the reaction mixture wasfiltered, concentrated, and purified by silica chromatography (100% DCMto 50% MeOH in DCM) to give tert-butyl6-(3-isopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 14 were used instead of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate:

-   tert-butyl    6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1    s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    s,3R)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

C. Preparation of5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-pivalamidocyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide(Example 135)

In a microwave vial were placedN-((1s,3s)-3-(6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-2-oxoindolin-1-yl)cyclobutyl)pivalamide(83 mg, 0.5 mmol), 5-amino-N,2-dimethylbenzamide (103 mg, 0.2 mmol),RuPhos Pd G1 Methyl t-Butyl Ether Adduct (10 mg, 0.01 mmol), and Cs₂CO₃(130 mg, 0.41 mmol) in dioxane (2 mL). The mixture was degassed withnitrogen, placed in the microwave reactor, and heated at 150° C. for 1h. Then it was purified by flash chromatography (100% EtOAc to 60% MeOHin EtOAc) to give5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-pivalamidocyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide.

Procedure 19: Preparation of the Compounds of Formula (16) According toReaction Scheme III

A. Preparation of 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine

A 500 mL pressure vessel equipped with a magnetic stir bar was chargedwith 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (10.0 g,38.8 mmol) followed by N-methylpyrrolidone (100 mL). The resultingsolution was treated with ammonium hydroxide solution (28% NH₃, 54 mL,390.0 mmol). The vessel was sealed, and the mixture stirred at 80° C. ina heating block for 48 h. The reaction mixture was then cooled to roomtemperature and carefully poured into water (900 mL). The mixture wasfurther cooled in an ice bath with stirring, and then the mixture wasfiltered to afford 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

B. Preparation of6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

A suspension of 1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(736 mg, 1.41 mmol),6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine (300 mg, 1.18mmol), and tetrakis(triphenylphosphine)palladium (136 mg, 118 umol) in1:1 DMF/DME (12 mL) was treated with 2 M aqueous Na₂CO₃ (4.1 mL, 8.2mmol). The mixture was sparged with N₂ for 1 min, then sealed andstirred vigorously at 120° C. overnight. The reaction mixture was cooledto room temperature, diluted with water, and extracted three times withEtOAc. The combined organic layers were concentrated under vacuum andpurified via flash chromatography on silica gel with gradient elution(0-100% EtOAc/hexanes followed by 0-100% MeOH/DCM) to afford6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 6, 7, 8, 9, 12, or 35 were usedinstead of1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

-   6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

-   1-((1 S,3    s)-3-((1R,4S)-2-Azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethylindolin-2-one

-   6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

-   6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

-   6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

-   1′-acetyl-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

-   tert-butyl    6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

C. Preparation of6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1s,3 S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

In a microwave vial were placed1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(130 mg, 0.242 mmol),6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine (62 mg, 0.242mmol), palladium tetrakis (28 mg, 0.024 mmol), and cesium carbonate (154mg, 0.726 mmol) in DMAc (2 mL) and water (0.4 mL). The mixture wasdegassed with N₂, sealed, and heated to 90° C. for 2 h., partitionedbetween EtOAc and water, and then extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered, concentrated in vacuo,and purified by flash chromatography (DCM/MeOH/NEt₃) to give6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

Procedure 20: Preparation of the Compounds of Formula I According toReaction Scheme III

A. Preparation of5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide(Example 136)

To a mixture of 5-bromo-N-isopropyl-2-methylbenzamide (44 mg, 0.171mmol),6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one(80 mg, 0.114 mmol), Pd₂(dba)₃ (11 mg, 0.011 mmol), Xantphos (13 mg,0.023 mmol) and Cs₂CO₃ (186 mg, 0.571 mmol) was added freshly degasseddioxane. The reaction mixture was heated to 90° C. and stirredovernight. The reaction was subsequently diluted with water andextracted with EtOAc. The combined organic layers were dried over MgSO₄,filtered, concentrated, and purified by silica chromatography (0-80%MeOH/DCM with 0.5% NEt₃) and HPLC (0-75% ACN/H₂O) to give5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 19 were used instead of        6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one;        and/or    -   the benzamides listed under Procedure 28, were used instead of        5-bromo-N-isopropyl-2-methylbenzamide:

Structure Example #

137

138

139

140

141

142

143

144

-   Commercially available methyl 5-bromo-2,4-difluorobenzoate and    1′-acetyl-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one    were used instead of 5-bromo-N-isopropyl-2-methylbenzamide and    6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1    s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one, respectively, to    prepare methyl    5-((6-(1′-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoate

-   Commercially available methyl 5-bromo-2,4-difluorobenzoate was used    instead of 5-bromo-N-isopropyl-2-methylbenzamide to prepare methyl    5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoate

-   5-Bromo-4-fluoro-N-isopropyl-2-methylbenzamide and tert-butyl    6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate    were used instead of 5-bromo-N-isopropyl-2-methylbenzamide and    6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one,    respectively, to prepare tert-butyl    6-(4-((2-fluoro-5-(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   5-bromo-N-ethyl-4-fluoro-2-methylbenzamide and tert-butyl    6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate    were used instead of 5-bromo-N-isopropyl-2-methylbenzamide and    6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one,    respectively, to prepare tert-butyl    6-(4-((5-(ethylcarbamoyl)-2-fluoro-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

B. Preparation of5-((6-(1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide(Example 145)

In a microwave vial were placed1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethylindolin-2-one(85.21 mg, 0.18 mmol),5-bromo-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide(46 mg, 0.14 mmol), Pd₂(dba)₃×CHCl₃ (6.19 mg, 0.01 mmol), Xanthphos(7.83 mg, 0.01 mmol), and Cesium carbonate, 99.9% (132.2 mg, 0.41 mmol)in dioxane (1 mL). The mixture was degassed with nitrogen, placed in themicrowave reactor, and heated at 150° C. for 30 min. The mixture waspurified by silica chromatography (100% DCM to 100% MeOH) and reversephase chromatography to give 5-((6-(1-((1 S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

Procedure 21: Preparation of the Compounds of Formula I According toReaction Scheme I

A. Preparation of tert-butyl6-(4-((2-fluoro-4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

In a flask were placed tert-butyl1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(192 mg, 0.33 mmol),5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N,2-dimethylbenzamide(115 mg, 0.27 mmol), Pd(PPh₃)₄ (22 mg, 0.02 mmol), and sodium carbonate(116 mg, 1.0 mmol) in DME (3 mL), and water (1 mL). The reaction mixturewas purged with nitrogen gas, and heated at 120° C. in a microwavereactor for 25 min. The reaction was filtered through a pad of celitewith MeOH, concentrated, and purified by reverse phase HPLC to givetert-butyl6-(4-((2-fluoro-4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 3 or 34 were used instead        of        5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N,2-dimethylbenzamide;        and/or    -   the compounds listed under Procedure 9 were used instead of        tert-butyl        1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate:

-   tert-butyl    6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(3,3,5,5-tetramethylpiperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl 1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-6-(3-isopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-6-(3-isopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(3-isopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1    S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

-   tert-butyl    1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(3-isopropyl-4-(3-(methoxycarbonyl)-4-methylphenoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

Procedure 22: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of4-fluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

To a solution of tert-butyl6-(4-((2-fluoro-4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate(110 mg, 0.14 mmol) in dichloromethane (1 mL) was added 4N HCl indioxane (0.5 mL). After stirring at room temperature for 2 h, thereaction mixture was concentrated under reduced pressure to give4-fluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 18, 20, or 21 were used instead oftert-butyl6-(4-((2-fluoro-4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate:

-   5-((3-cyclopropyl-6-(1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-cyclopropyl-6-(2-oxo-1-((1s,3s)-3-(3,3,5,5-tetramethylpiperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-cyclopropyl-6-(1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((6-(1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-cyclopropyl-6-(1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((6-(1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-cyclopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((6-(1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-((S)-sec-butyl)-6-(1-((1    S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-((S)-sec-butyl)-6-(2-oxo-1-((1    s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   5-((3-((S)-sec-butyl)-6-(1-((1    s,3R)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

-   4-Fluoro-5-((6-(1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide

-   N-Ethyl-4-fluoro-5-((6-(1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide

-   methyl    5-((6-(1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate

Procedure 23: Preparation of the Compounds of Formula I According toReaction Scheme IV

A. Preparation of5-((6-(1′-(2-hydroxy-2-methylpropanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 146)

To a solution of5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide (0.10 g, 0.11 mmol) in DMF (1 mL)were added 2-hydroxy-2-methylpropanoic acid (0.024 g, 0.23 mmol), DIEA(0.2 mL, 1.1 mmol) and HATU (0.087 g, 0.23 mmol). The resulting mixturewas stirred at room temperature for 30 minutes, and then quenched withwater and extracted with EtOAc. The combined organic layers were washedwith brine, dried (Na₂SO₄), concentrated, and purified by reverse phasechromatography (0.01% TFA in ACN/0.01% TFA in Water) to give5-((6-(1′-(2-hydroxy-2-methylpropanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 22 were used instead of        5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide;        and/or    -   the carboxylic acids, that are commercially available or can be        made by methods known in the art, such as (R)-2-hydroxypropanoic        acid, 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid,        1-methylcyclobutane-1-carboxylic acid, and        1-methylcyclopropane-1-carboxylic acid were used instead of        2-hydroxy-2-methylpropanoic acid:

Structure Example #

147

148

149

150

151

B. Preparation of5-((3-isopropyl-6-(1′-(1-methylcyclopropane-1-carbonyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 152)

To a solution of5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(0.11 g, 0.11 mmol) in DMF (1 mL) were added1-methylcyclopropane-1-carboxylic acid (0.023 g, 0.23 mmol), DIEA (0.2mL, 1.1 mmol) and a 50% solution of propylphosphonic anhydride (T3P) inEtOAc (0.14 mL, 0.23 mmol). The resulting mixture was stirred at roomtemperature for 30 minutes, and then quenched with water and extractedwith EtOAc. The combined organic layers were washed with brine, dried(Na₂SO₄), concentrated, and purified by silica chromatography (10% NH₄OHin MeOH/EtOAc/hexanes) followed by reverse phase chromatography (0.01%TFA in ACN/0.01% TFA in Water) to give5-((3-isopropyl-6-(1′-(1-methylcyclopropane-1-carbonyl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 22 were used instead of        5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide;        and/or    -   the carboxylic acids, that are commercially available or can be        made by methods known in the art, such as        1-methylcyclopropane-1-carboxylic acid, oxetane-3-carboxylic        acid, 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid,        cyclobutanecarboxylic acid, and        bicyclo[1.1.1]pentane-1-carboxylic acid were used instead of        2-hydroxy-2-methylpropanoic acid:

Structure Example #

153

154

155

156

Procedure 24: Preparation of the Compounds of Formula I According toReaction Scheme

A. Preparation of 5-((6-(1′-acetyl-1-((1S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-((S)-sec-butyl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 157)

To a mixture of 5-((3-((S)-sec-butyl)-6-(1-((1S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(45 mg, 0.07 mmol) and triethylamine (0.1 ml, 0.64 mmol) indichloromethane (2 mL) was added acetic anhydride (0.01 ml, 0.1 mmol).After stirring at room temperature for 20 min, the reaction mixture wasconcentrated under reduced pressure and purified by reverse phase HPLCto afford5-((6-(1′-acetyl-1-((1S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-((S)-sec-butyl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 22 were used instead of        5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide;        and/or    -   Alkylsulfonyl chlorides, such as cyclopropanesulfonyl chloride        and methanesulfonyl chloride, were used instead of acetic        anhydride:

Structure Example #

158

159

160

161

162

163

164

165

166

167

168

169 Methyl chloroformate was used instead of acetic anhydride to preparethis compound

-   methyl    5-((6-(1′-acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate

-   methyl    5-((6-(1′-acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate

Procedure 25: Preparation of the Compounds of Formula I According toReaction Scheme IV

A. Preparation of 4-fluoro-5-((6-(1-((1 S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 170)

To a mixture of4-fluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(70 mg, 0.10 mmol) and 3-oxetanone (21 mg, 0.30 mmol) in methanol (3 mL)was added zinc chloride (21 mg, 0.15 mmol) followed by sodiumcyanoborohydride (19 mg, 0.30 mmol). The mixture was sealed and heatedat 50° C. for 16 h., then cooled, quenched with saturated aqueous sodiumbicarbonate, and extracted with dichloromethane. The combined organiclayers were dried over sodium sulfate, filtered, concentrated, andpurified on Gilson reverse phase HPLC to give 4-fluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   5-((3-cyclopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide        was used instead of 4-fluoro-5-((6-(1-((1 S,3        s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide;        and/or    -   N-ethyl-4-fluoro-5-((6-(1-((1 S,3        s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide        and        4-fluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide        were used instead of 4-fluoro-5-((6-(1-((1 S,3        s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide;        and/or    -   4-fluoro-5-((6-(1-((1 S,3        s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide:

Ex- Structure ample #

171

172

173

Procedure 26: Preparation of the Compounds of Formula I According toReaction Scheme II

A. Preparation of5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoicacid

To a stirring solution of methyl5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate(430 mg, 0.69 mmol) in THF (20 ml) and MeOH (10 ml) was added LiOH.H₂O(33 mg, 1.39 mmol). The resulting mixture was warmed to 40° C. and thenstirred for 2 days. After cooling to room temperature, the reactionmixture was concentrated to give5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoicacid, which was used in the next step without further purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   NaOH was used instead of LiOH; and/or    -   Methyl        5-((6-(1′-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2,4-difluorobenzoate        was used instead of methyl        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate;        and/or    -   Methyl        5-((6-(1′-acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate        was used instead of methyl        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate;        and/or    -   methyl        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoate        was used instead of methyl        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate:

-   5-((6-(1′-Acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic    acid

-   5-((6-(1′-Acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoic    acid

-   5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic    acid

B. Preparation of5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamide(Example 174)

To a stirring solution of5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoicacid (1.45 g, 2.4 mmol) in DMF (5 ml) were added1-(fluoromethyl)cyclopropan-1-aminehydrochloride (300 mg, 2.4 mmol),HATU (1.8 g, 4.7 mmol), and DIEA (2.5 ml, 14.4 mmol). The resultingmixture was stirred until the starting material was sufficientlyconsumed. The reaction solution was quenched with water and the aqueouslayer was extracted with EtOAc. The combined organic layer was washedwith brine, dried over Na₂SO₄, concentrated, and purified by reversephase chromatography (ACN/water) to give5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic        acid was used instead of        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic        acid; or    -   5-((6-(1-acetyl-2′-oxo-1′-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[azetidine-3,3′-indolin]-6′-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic        acid was used instead of 5-((6-(3,3-dimethyl-2-oxo-1-((1        s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic        acid; or    -   5-((6-(1′-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic        acid was used instead of        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic        acid; or    -   5-((6-(1′-acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoic        acid was used instead of        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic        acid; or    -   5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic        acid was used instead of        5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic        acid; and    -   The commercially available amines, such as methylamine,        ethylamine, and isopropylamine, were used instead of        1-(fluoromethyl)cyclopropan-1-aminehydrochloride:

Ex- Structure ample #

175

176

177

178

179

180

181

182

Procedure 27: Preparation of the Compounds of Formula (8) According toReaction Scheme I A. Preparation of5-amino-4-fluoro-N-(1-(methoxymethyl)cyclopropyl)-2-methylbenzamide

To a mixture of 5-amino-4-fluoro-2-methylbenzoic acid (200.0 mg, 1.2mmol), 1-(methoxymethyl)cyclopropan-1-amine (235.4 mg, 2.4 mmol), andDIPEA (1.0 mL, 5.9 mmol) was added T3P (1.4 mL, 2.4 mmol). Afterstirring at room temperature for 48 h, the reaction was quenched withwater and the organic layers were extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried (Na₂SO₄), andconcentrated to give5-amino-4-fluoro-N-(1-(methoxymethyl)cyclopropyl)-2-methylbenzamide,which was used in the next step without purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the amines indicated below were used instead of        1-(methoxymethyl)cyclopropan-1-amine; and/or    -   the benzoic acids indicated below were used instead of        5-amino-4-fluoro-2-methylbenzoic acid:

iso-Propylamine and 5-amino-2-methylbenzoic acid were used to prepare5-amino-N-isopropyl-2-methylbenzamide

(R)-Butan-2-amine was used to prepare(R)-5-amino-N-(sec-butyl)-4-fluoro-2-methylbenzamide

-   (S)-Butan-2-amine was used to prepare    (S)-5-amino-N-(sec-butyl)-4-fluoro-2-methylbenzamide

-   2-Methoxyethan-1-amine was used to prepare    5-amino-4-fluoro-N-(2-methoxyethyl)-2-methylbenzamide

-   Cyclopropanamine was used to prepare    5-amino-N-cyclopropyl-4-fluoro-2-methylbenzamide

-   iso-Propylamine and 5-amino-2-chloro-4-fluorobenzoic acid were used    to prepare 5-amino-2-chloro-4-fluoro-N-isopropylbenzamide

-   cyclo-Propylamine and 5-amino-2-methylbenzoic acid were used to    prepare 5-amino-N-cyclopropyl-2-methylbenzamide

-   Methylamine and 5-amino-2,3-dimethylbenzoic acid were used to    prepare 5-amino-N,2,3-trimethylbenzamide

-   Methylamine and 5-amino-2-chloro-4-fluorobenzoic acid were used to    prepare 5-amino-N,2,3-trimethylbenzamide

B. Preparation of 3-amino-4-fluoro-N-methylbenzamide

To a mixture of 3-amino-4-fluorobenzoic acid (100.0 mg, 0.7 mmol) andTEA (0.2 mL, 1.4 mmol) in DMF (2 mL) was added HATU (367.67 mg, 0 mol)followed by methylamine in 1 M THF (1.9 mL, 1.9 mmol). After stirring atroom temperature overnight, the reaction was quenched with water and theorganic layers were extracted with EtOAc. The combined organic layerswere washed with water and brine, dried (Na₂SO₄), and concentrated togive 3-amino-4-fluoro-N-methylbenzamide, which was used in the next stepwithout purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the amines indicated below were used instead of methylamine;        and/or    -   the benzoic acids indicated below were used instead of        3-amino-4-fluorobenzoic acid:

-   iso-Propylamine and 5-amino-4-fluoro-2-methylbenzoic acid were used    to prepare 5-amino-4-fluoro-N-isopropyl-2-methylbenzamide

-   1-(Fluoromethyl)cyclopropan-1-amine and    5-amino-4-fluoro-2-methylbenzoic acid were used to prepare    5-amino-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamide

-   Ethylamine and 5-amino-2-methylbenzoic acid were used to prepare    5-amino-N-ethyl-2-methylbenzamide

-   Oxetan-3-amine and 5-amino-2-methylbenzoic acid were used to prepare    5-amino-2-methyl-N-(oxetan-3-yl)benzamide

-   2-Aminoethan-1-ol and 5-amino-2-methylbenzoic acid were used to    prepare 5-amino-N-(2-hydroxyethyl)-2-methylbenzamide

-   2-Methoxyethan-1-amine and 5-amino-2-methylbenzoic acid were used to    prepare 5-amino-N-(2-methoxyethyl)-2-methylbenzamide

Procedure 28: Preparation of the Compounds of Formula I According toReaction Scheme III A. Preparation of5-bromo-N-isopropyl-2-methylbenzamide

To a solution of 5-bromo-2-methylbenzoic acid (0.50 g, 2.33 mmol), HATU(1.77 g) and isopropylamine (0.499 mL, 5.81 mmol) in DMF (5 mL) wasadded DIPEA (1.01 mL, 5.81 mmol). The reaction was stirred at roomtemperature for 5 hours. Water was added to the reaction mixture and theresulting precipitate was isolated by filtration and washed with asolution of 1N HCl to give 5-bromo-N-isopropyl-2-methylbenzamide.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the amines indicated below were used instead of isopropylamine;        and/or    -   the benzoic acids indicated below were used instead of        5-bromo-2-methylbenzoic acid

-   Ethylamine was used to prepare 5-bromo-N-ethyl-2-methylbenzamide

-   iso-Butylamine was used to prepare    5-bromo-N-isobutyl-2-methylbenzamide

-   2-Methoxyethan-1-amine was used to prepare    5-bromo-N-(2-methoxyethyl)-2-methylbenzamide

-   Methylamine and 5-bromo-2-(trifluoromethoxy)benzoic acid were used    to prepare 5-bromo-N-methyl-2-(trifluoromethoxy)benzamide

-   Methylamine and 5-bromo-2-(trifluoromethyl)benzoic acid were used to    prepare 5-bromo-N-methyl-2-(trifluoromethyl)benzamide

-   Methylamine and 5-bromo-2-cyclopropylbenzoic acid were used to    prepare 5-bromo-2-cyclopropyl-N-methylbenzamide

-   Methylamine and 5-bromo-2-ethylbenzoic acid were used to prepare    5-bromo-2-ethyl-N-methylbenzamide

-   5-bromo-4-fluoro-2-methylbenzoic acid was used to prepare    5-bromo-4-fluoro-N-isopropyl-2-methylbenzamide

-   Ethylamine and 5-bromo-4-fluoro-2-methylbenzoic acid were used to    prepare 5-bromo-N-ethyl-4-fluoro-2-methylbenzamide

-   1-(Difluoromethyl)cyclopropan-1-amine and    5-bromo-3,4-difluoro-2-methylbenzoic acid were used to prepare    5-bromo-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide

Procedure 29: Preparation of the Compounds of Formula (26) According toReaction Scheme VII

A. Preparation of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

To a stirring solution of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one (1.3 g, 4.16 mmol)in AcOH (7.0 ml) were added piperidine (2.1 ml, 20.8 mmol) and TMS-CN(1.0 ml, 8.3 mmol) at 0° C. The reaction mixture was warmed to roomtemperature and then stirred for an additional 15 h. The reactionmixture was concentrated and the residue was re-dissolved in EtOAc andthe organic layer was washed with satd. NaHCO₃, water followed by brine,dried over Na₂SO₄, concentrated, and purified by flash chromatography(Hexanes/EtOAc) to afford(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

B. Preparation of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

To a stirring solution of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile(300 mg, 0.75 mmol) in THF (10 ml) was added 1.0 M MeMgBr (2.2 ml, 2.24mmol, THF) at 0° C. The resulting mixture was allowed to warm to roomtemperature and then stirred for an additional 15 h. The reactionmixture was quenched with satd. NH₄Cl and the aqueous layer wasextracted with EtOAC. The combined organic layer was washed with brine,dried over Na₂SO₄, concentrated, and purified by flash chromatography(Hexanes/EtOAc) to afford6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

Procedure 30: Preparation of the Compounds of Formula (23) According toReaction Scheme VII

A. Preparation of(4-((3-carbamoyl-4-methylphenyl)amino)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)boronicacid

To a stirring solution of5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide(200 mg, 0.52 mmol) in Dioxane (20 ml) were added bis(pinacolato)diboron(263 mg, 1.0 mmol), KOAc (102 mg, 1.0 mmol), and Pd(dppf)Cl₂.DCM (42 mg,0.052 mmol). The resulting suspension was degassed by bubbling argon gasthrough (2 min), sealed, and then heated at 90° C. for 15 h. Thereaction mixture was cooled to room temperature, filtered, andconcentrated to give(4-((3-carbamoyl-4-methylphenyl)amino)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)boronicacid, which was used in the next step without further purification.

Procedure 31: Preparation of the Compounds of Formula I According toReaction Scheme VII

A. Preparation of5-((3-cyclopropyl-6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide(Example 183)

To a solution of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one(40 mg, 0.026 mmol) in DME (3 ml) were added Pd(PPh₃)₄ (2.0 mg, 0.002mmol), 2M Na₂CO₃ (0.06 ml, 0.12 mmol), and(4-((3-carbamoyl-4-methylphenyl)amino)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)boronicacid (18 mg, 0.051 mmol). The resulting suspension was degassed bybubbling Ar gas, sealed, then heated at 120° C. for 30 min. The reactionmixture was cooled to room temperature then diluted with EtOAc. Theorganic layer was washed with water, brine, dried over Na₂SO₄,concentrated, and purified by flash chromatography (Hex/EtOAc) to afford5-((3-cyclopropyl-6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide.

The following compound was prepared using a similar procedure except6-bromo-3,3-difluoro-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one:

Structure Example #

184

Procedure 32: Preparation of the Compounds of Formula (13) Shown inReaction Scheme I

A. Preparation of tert-butyl3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate

To a stirring solution of 1-(tert-butyl) 3-methylazetidine-1,3-dicarboxylate (12.5 g, 58.1 mmol, commercially available)and 2-bromo-5-chloroaniline (10 g, 48.4 mmol) in DCM (200 ml) was addedtrimethylaluminum (2.0 M in toluene, 34 ml, 68 mmol) at 0° C. Theresulting mixture was heated at 40° C. for overnight. After the startingmaterial was consumed, the reaction mixture was cool to 0° C. thenquenched with water. The aqueous layer was extracted with DCM and thecombined organic layer was dried over Na₂SO₄, concentrated, and purifiedby flash chromatography (Hexane/EtOAc) to give tert-butyl3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate.

B. Preparation of tert-butyl3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate

To a stirring solution of tert-butyl3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate (10 g, 25.7mmol) in ACN (200 ml) were added K₂CO₃ (10.6 g, 77 mmol) and PMBCl (3.83ml, 28.2 mmol) at room temperature. The resulting mixture was warmed to85° C. and stirred overnight. Then the resulting suspension was cooledand filtered. The filtrate was concentrated and purified by flashchromatography (Hexane/EtOAc) to afford tert-butyl3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate.

C. Preparation of tert-butyl6′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate

To a stirring solution of tert-butyl3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1-carboxylate(6 g, 11.8 mmol) in dioxane (20 mL) were added PCy₃ (0.165 g, 0.588mmol), Pd(OAc)₂ (0.132 g, 0.588 mmol), and sodium tertbutoxide (3.39 g,35.3 mmol) at room temperature. The resulting mixture was degassed bybubbling argon gas through for 3 minutes. The reaction vessel was sealedand heated at 80° C. for 15 min. After cooling to room temperature, thereaction mixture was quenched with saturated NH₄Cl solution. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₃, and concentrated to give tert-butyl6′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate,which was used in the next step without further purification.

D. Preparation of6′-chloro-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indolin]-2′-one

To a stirring solution of tert-butyl6′-chloro-1′-(4-methoxybenzyl)-2′-oxospiro[azetidine-3,3′-indoline]-1-carboxylate(5.05 g, 11.8 mmol) in methanol (50 ml) was added 4 M HCl in dioxane(14.7 ml, 58.9 mmol). The reaction mixture was stirred overnight andthen concentrated. The resulting residue was redissolved with theminimum amount of DCM and then added into a stirring Et₂O. Thesuspension was stirred for additional 30 minutes, filtered, washed withEt₂O, and dried to give6′-chloro-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indolin]-2′-one.

E. Preparation of1-acetyl-6′-chloro-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indolin]-2′-one

To a stirring solution of6′-chloro-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indolin]-2′-one (2.23g, 6.11 mmol) in DCM (20 ml) were added acetic anhydride (0.866 ml, 9.16mmol) and triethylamine (8.51 ml, 61.1 mmol) at room temperature. After10 min, the reaction mixture was concentrated and purified by flashchromatography to give1-acetyl-6′-chloro-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indolin]-2′-one.

F. Preparation of 1-acetyl-6′-chlorospiro[azetidine-3,3′-indolin]-2′-one

To a stirring solution of1-acetyl-6′-chloro-1′-(4-methoxybenzyl)spiro[azetidine-3,3′-indolin]-2′-one.(0.7 g, 1.89 mmol) in DCM (10 ml) were added TfOH (0.835 ml, 9.44 mmol)and TFA (7.22 ml, 94.4 mmol) at room temperature. The reaction mixturewas stirred overnight and then concentrated. The residue was dissolvedwith EtOAc. The organic layer was washed with sat. NaHCO₃ and brine,dried over Na₂SO₄, concentrated, and purified by flash chromatography(DCM/MeOH) to give1-acetyl-6′-chlorospiro[azetidine-3,3′-indolin]-2′-one.

G. Preparation of1-acetyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one

To a stirring solution of1-acetyl-6′-chlorospiro[azetidine-3,3′-indolin]-2′-one (0.35 g, 1.4mmol) in dioxane were added bis(pinacolato)diboron (1.06 g, 4.19 mmol),potassium acetate (0.411 g, 4.19 mmol), Pd₂dba₃ (77 mg, 0.084 mmol), andXantphos (100 mg, 0.209 mmol). The resulting suspension was degassed bybubbling argon gas through for 5 minutes. The reaction vessel was sealedand then heated at 100° C. for overnight. After cooling to roomtemperature, the reaction mixture was concentrated to give1-acetyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one,which was used in the next step without further purification.

H. Preparation of1-acetyl-1′-(3-oxocyclobutyl)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one

To a stirring solution of1-acetyl-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one(0.478 g, 1.4 mmol) in NMP (5 mL) were added bromocyclobutanone (0.495ml, 5.58 mmol) and K₂CO₃ (0.964 g, 6.68 mmol) at room temperature. Theresulting mixture was warmed to 50° C. and stirred overnight. After allthe starting material was consumed, the reaction mixture was cooled toroom temperature and then filtered. The filtrate was diluted with EtOAc.The organic layer was washed with water followed by brine, dried overNa₂SO₄, and concentrated to give1-acetyl-1′-(3-oxocyclobutyl)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one,which was used in the next step without further purification.

I. Preparation of1-acetyl-1′-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one

To a solution of1-acetyl-1′-(3-oxocyclobutyl)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indoline]-2′-one(1 g, 2.44 mmol) and piperidine (0.96 ml, 9.75 mmol) in DCM (10 ml) wereadded acetic acid, ACS reagent (0.88 ml, 14.62 mmol) and sodiumtriacetoxyborohydride (1.55 g, 7.31 mmol). After the mixture was stirredfor 2 h at room temperature, the mixture was quenched with sat. NaHCO₃and extracted with DCM. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to give1-acetyl-1′-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one,which was used in the next step without further purification.

Procedure 33: Preparation of the Compounds of Formula (27) According toReaction Scheme VI

A. Preparation of5-((6-(1-acetyl-2′-oxo-1′-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[azetidine-3,3′-indolin]-6′-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid

To a mixture of1-acetyl-1′-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidine-3,3′-indolin]-2′-one(0.5 g, 1.04 mmol),5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid (0.25 g, 0.63 mmol) and Pd(PPh₃)₄ (120.51 mg, 0.1 mmol) in a sealtube was added 2M Na₂CO₃ (3.65 ml) and DME (10 ml). After the mixturewas heated at 90° C. for 1 h, the mixture was diluted with EtOAc andwater. To the resulting mixture was added citric acid to adjust the pHto ca. 6. The organic layers were extracted with DCM, and the combinedorganic layers were concentrated and purified by flash chromatography(100% DCM to 100% MeOH) to afford5-((6-(1-acetyl-2‘-oxo-l’-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[azetidine-3,3′-indolin]-6′-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid.

Procedure 34: Preparation of the Compounds of Formula (9) Shown inReaction Scheme I

A. Preparation of methyl5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate

To a mixture of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine(150 mg, 0.58 mmol) and methyl 5-hydroxy-2-methylbenzoate in DMF (3 mL)was added cesium carbonate (568 mg, 1.7 mmol). After stirring for 1 h at100° C., the reaction was filtered and concentrated under reducedpressure. The residue was purified by reverse phase HPLC give methyl5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate.

The following compound was prepared using a similar procedure except6-bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine and potassiumcarbonate were used instead of6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine and cesiumcarbonate, respectively:

-   Methyl    5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate

The following compound was prepared using a similar procedure except6-bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine,5-hydroxy-2-methylbenzamide, and potassium carbonate were used insteadof 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine, methyl5-hydroxy-2-methylbenzoate, and cesium carbonate, respectively:

-   5-((6-Bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzamide

B. Preparation of5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoicacid

In a vial were placed methyl5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate(784.4 mg, 2.0 mmol) and lithium hydroxide (818 mg, 20 mmol) in THF (10mL)/water (5 mL). The mixture was heated at 60° C. for 16 h, cooled toroom temperature, concentrated, and used in the next step withoutpurification.

C. Preparation of5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-N,2-dimethylbenzamide

In a vial were placed5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoicacid (769 mg, 2.0 mmol), methylamine hydrochloride (668 mg, 9.9 mmol),diethylisopropylamine (4.2 mL, 24 mmol), and HATU (3774 mg, 9.9 mmol) inACN (20 mL). The mixture was stirred at room temperature for 1 h. Thenthe mixture was quenched with water and extracted with EtOAc. Thecombined organic layers were washed with brine, dried, concentrated, andpurified by flash chromatography (100% Hexane to 100% EtOAc then 100%DCM to 100% MeOH) to give5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-N,2-dimethylbenzamide.

Procedure 35: Preparation of the Compounds of Formula (13) According toReaction Scheme I

A. Preparation of3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline

In a 20 mL vial was placed3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(490 mg, 1.15 mmol) in Toluene (5 ml). To this was added Red-A1 60% wt.in Toluene (563.25 μl, 2.89 mmol). The mixture was heated at 85° C. for2 h, and then quenched with sat. NaHCO₃. To this was added Na₂SO₄ andthe mixture was stirred at room temperature for 1 h, and then filtered.The filtrate was concentrated and used in the next step without furtherpurification.

Procedure 36: Preparation of the Compounds of Formula (13) According toReaction Scheme I

A. Preparation of1-((1s,3s)-3-(benzhydrylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a stirring solution of3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(10 g, 28.1 mmol), diphenylmethanamine (9.7 ml, 56.3 mmol), and aceticacid (4.87 ml, 84.5 mmol) in DCE (100 ml) was added Na(OAc)₃ (8.9 g,42.2 mmol). The resulting suspension was stirred overnight then quenchedwith satd. NaHCO₃. The mixture was filtered and then the aqueous layerwas extracted with DCM. The combined organic layer was dried overNa₂SO₄, filtered, then concentrated to give1-((1s,3s)-3-(benzhydrylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one,which was used in the next step without further purification.

B. Preparation of1-((1s,3s)-3-aminocyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a solution of1-((1s,3s)-3-(benzhydrylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(23.2 g) in MeOH (30 ml) in Parr bottle was added Pd/C (10% w/w, 3.0 g,2.8 mmol). Then the bottle was attached to Parr shaker, charged with H₂(40 psi), and shaken overnight. The resulting suspension was filteredthrough celite then concentrated to give crude product. The residue wasredissolved with Et₂O (200 ml) and 4 N HCl (dioxane, 28.2 ml, 112.6mmol) was added slowly at 0° C. while stirring. After 30 min, theresidue was filtered and dried to give1-((1s,3s)-3-aminocyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

C. Preparation ofN-((1s,3s)-3-(3,3-dimethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)cyclobutyl)pivalamide

To a solution of1-((1s,3s)-3-aminocyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(2.9 g, 6.9 mmol) and triethylamine (4.8 mL, 34.6 mmol) in DCM (70 mL)was added pivaloyl chloride dropwise over 10 min. The reaction mixturewas stirred at room temperature for 1 h. Then the reaction mixture wasloaded on a silica gel column and purified (100% Hexane to 60% EtOAc inHexane) to giveN-((1s,3s)-3-(3,3-dimethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)cyclobutyl)pivalamide.

Procedure 37: Preparation of the Compounds of Formula (14) According toReaction Schemes II and IV

A. Preparation of6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-11′-pivaloylspiro[indoline-3,4′-piperidin]-2-one

To a suspension of6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(0.092 g, 0.16 mmol) in DCM (2 mL) was added triethylamine (0.23 mL, 1.6mmol) followed by pivaloyl chloride (0.03 mL, 0.24 mmol). The resultingmixture was stirred at room temperature for 3 h and then was quenchedwith water and extracted with DCM. The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated to give6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1′-pivaloylspiro[indoline-3,4′-piperidin]-2-one,which was used in the next step without further purification.

Procedure 38: Preparation of 5-bromo-3,4-difluoro-2-methylbenzoic acid

To a solution of tetramethylpiperidine (2.67 mL, 15.8 mmol) in THF (10mL) at 0° C. was steadily dropwise added n-butyllithium (6.60 mL, 15.2mmol). The mixture was stirred for 15 min. Then the mixture was dropwiseadded to a solution of 3-bromo-4,5-difluorobenzoic acid (1.50 g, 6.33mmol) in THF (90 mL) at −78° C. The resulting reaction mixture wasstirred at −78° C. for 30 min followed by the addition of iodomethane(1.97 mL, 31.7 mmol). The reaction mixture was slowly warmed to roomtemperature and stirred at room temperature for 16 h. The mixture wasquenched with H₂O, acidified with 2 M HCl, and extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered, concentrated,and used in the next step without further purification.

Procedure 39: Preparation of5-amino-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide

In a vial were placed5-bromo-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide(100 mg, 0.29 mmol), Pd₂(dba)₃ (13 mg, 0.015 mmol), XantPhos (17 mg,0.029 mmol), benzophenone imine (0.055 mL, 0.33 mmol), and cesiumcarbonate (287 mg, 0.88 mmol) in dioxane (2 mL). The mixture wasdegassed with argon and was heated at 90° C. for 18 h. After cooling toroom temperature, the mixture was poured into water and extracted withethyl acetate. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated under reduced pressure. Theresulting imine intermediate was dissolved in THF (3 mL) followed by theaddition of 2 M HCl in water (1.1 ml). The mixture was stirred at roomtemperature for 3 hours and then concentrated in vacuo. To the resultingresidue were added ethyl acetate and sat. NaHCO₃. The layers wereseparated and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried (MgSO₄), filtered, concentrated, andpurified by flash chromatography (0.5% NEt₃ in DCM/MeOH) to give5-amino-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

Chiral Resolution

-   1. Separation of the isomers of    5-((6-(1-((1s,3s)-3-(3-(difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

5-((6-(1-((1s,3s)-3-(3-(difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 104) was separated on CHIRALPAK IA SFC 5 um 21×250 mm column in35% MeOH (modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the twosingle isomers:

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(3-CHIRALPAK IA 1^(st) eluting Example (difluoromethyl) SFC 5 um peak 104Apyrrolidin-1-yl) 21 × 250 mm 2^(nd) eluting Example cyclobutyl)- columnin 35% peak 104B 3,3-dimethyl- MeOH (modified 2-oxoindolin-6-yl)- with10 mM 3-isopropyl-3H- NH₃)/CO₂ at imidazo[4,5-c]pyridin- 60 mL/min4-yl)amino)-N,2- dimethylbenzamide

-   2. Separation of the isomers of    5-((6-(1-((1s,3s)-3-(3-(difluoromethyl)piperidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

5-((6-(1-((1s,3s)-3-(3-(difluoromethyl)piperidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide(Example 105) was separated on CHIRALPAK IA SFC 5 um 21×250 mm column in35% MeOH (modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the twosingle isomers:

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(3-CHIRALPAK IA 1^(st) eluting Example (difluoromethyl)piperidin- SFC 5 umpeak 105A 1-yl)cyclobutyl)- 21 × 250 mm 2^(nd) eluting Example3,3-dimethyl- column in 35% peak 105B 2-oxoindolin-6-yl)- MeOH (modified3-isopropyl-3H- with 10 mM imidazo[4,5-c]pyridin- NH₃)/CO₂ at4-yl)amino)-N,2- 60 mL/min dimethylbenzamide

-   3. Separation of the isomers of    N-(1,1-difluoropropan-2-yl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide

N-(1,1-difluoropropan-2-yl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide(Example 21) was separated on CHIRALPAK IC SFC 5 um 21×250 mm column in50% MeOH—NH₃ at 60 mL/min to give the two single isomers:

Name Separation method Peak # Example # N-(1,1-difluoropropan- CHIRALPAK1^(st) eluting Example 2-yl)-5-((6-(3,3- IC SFC peak 21Adimethyl-2-oxo-1- 5 um 21 × 250 2^(nd) eluting Example((1s,3s)-3-(piperidin-1- mm column peak 21B yl)cyclobutyl)indolin- in50% 6-yl)-3-isopropyl- MeOH—NH₃ 3H-imidazo[4,5-c] at 60 mL/minpyridin-4-yl)amino)-2- methylbenzamide

Procedure 40: Preparation of the Compounds of Formula 1 According toReaction Scheme VIII

A. Preparation of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

In a round bottomed flask were placed commercially available6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one (15 g, 62 mmol) andK₂CO₃ (13 g, 93 mmol) in acetonitrile (140 mL) under nitrogen. To thiswas slowly added 3-bromocyclobutanone (6.8 mL, 75 mmol). After stirringat room temperature for 1 h, the mixture was filtered, and the filtratewas concentrated. To the resulting solid was added acetonitrile. Afterstirring the mixture for 30 min, the precipitate was filtered to give6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

The following compounds were prepared using a similar procedure.

3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-one

3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-onewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine was usedinstead of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6′-Bromo-1′-(3-oxocyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one

6′-Bromo-1′-(3-oxocyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-onewas prepared using a similar procedure except that6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1¹H)-onewas used instead of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-bromo-4-(difluoromethyl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-onewas prepared using a similar procedure except that6-bromo-4-(difluoromethyl)-3,3-dimethylindolin-2-one was used instead of6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6′-bromo-1′-(3-oxocyclobutyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-1′-(3-oxocyclobutyl)spiro[cyclopropane-1,3′-indolin]-2′-one wasprepared using a similar procedure except that6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one was used instead of6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

B. Preparation of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

In a round bottomed flask was placed6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one(20 g, 65 mmol) in acetic acid (110 mL). To this were added piperidine(7.7 mL, 78 mmol) and TMS-CN (16 mL, 130 mmol) at 0° C. The reactionmixture was warmed to room temperature and stirred for 18 h. Then it wasconcentrated, diluted with EtOAc, and filtered. The solid wasre-dissolved in DCM, washed with sat. NaHCO₃ and brine, dried (Na₂SO₄),and concentrated to give(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

The following compounds were prepared using a similar procedure.

-   (i)    (1s,3s)-3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that3-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-onewas used instead of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (ii)    (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-morpholinocyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-morpholinocyclobutane-1-carbonitrilewas prepared using a similar procedure except that morpholine was usedinstead of piperidine.

-   (iii)    (1s,3s)-3-(6′-Bromo-2′-oxo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6′-Bromo-2′-oxo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that6′-bromo-1′-(3-oxocyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-onewas used instead of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (iv)    (1s,3s)-3-(6-Bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

C. Preparation of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(1,4-oxazepan-4-yl)cyclobutane-1-carbonitrile

In a 20 mL vial were placed6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)pyrrolo[3,2-b]pyridin-2-one (1.0g, 3.2 mmol), 1,4-oxazepane hydrochloride (0.53 g, 3.9 mmol), Ti(OiPr)₄(1.9 mL, 6.5 mmol) in AcOH (5 mL). After stirring at room temperaturefor 5 min, the mixture was cooled to 0° C. followed by the addition ofTMS-CN (0.81 mL, 6.5 mmol). The reaction mixture was warmed to roomtemperature and stirred for 16 h. Then, it was concentrated, dilutedwith DCM and sat. NaHCO₃, and extracted with DCM. The combined organiclayers were dried (Na₂SO₄), filtered through a pad of Celite,concentrated, and purified by flash chromatography (100% DCM to 100%EtOAc) to give(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(1,4-oxazepan-4-yl)cyclobutane-1-carbonitrile.

The following compounds were prepared using a similar procedure.

-   -   (i)        (1s,3s)-1-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except6-oxa-2-azabicyclo[3.2.1]octane hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   -   (ii)        (1s,3s)-1-(2-Oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(2-Oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except2-oxa-5-azabicyclo[2.2.2]octane hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   (iii)    (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except 5-azaspiro[2.5]octanehydrochloride was used instead of 1,4-oxazepane hydrochloride.

-   (iv)    (1s,3s)-1-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except 3-azabicyclo[3.2.0]heptanehydrochloride was used instead of 1,4-oxazepane hydrochloride.

-   (v)    (1s,3s)-1-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except 3-azabicyclo[4.1.0]heptanehydrochloride was used instead of 1,4-oxazepane hydrochloride.

-   (vi)    (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(2,2-dimethylmorpholino)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(2,2-dimethylmorpholino)cyclobutane-1-carbonitrilewas prepared using a similar procedure except 2,2-dimethylmorpholinehydrochloride was used instead of 1,4-oxazepane hydrochloride.

-   (vii)    (1s,3S)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutane-1-carbonitrile

(1s,3S)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure excepthexahydro-1H-furo[3,4-c]pyrrole hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   (viii)    (1s,3s)-1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except8-oxa-3-azabicyclo[3.2.1]octane hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   (ix)    (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except4-oxa-7-azaspiro[2.5]octane hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   (x)    (1s,3s)-1-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   (xi)    (1s,3s)-1-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except 3-azabicyclo[3.1.0]hexanehydrochloride was used instead of 1,4-oxazepane hydrochloride.

-   (xii)    (1s,3s)-1-(Azepan-1-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(Azepan-1-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except azepane was used insteadof 1,4-oxazepane hydrochloride.

-   (xiii)    (1s,3s)-1-(3-Azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(3-Azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except 3-azabicyclo[3.2.1]octanewas used instead of 1,4-oxazepane hydrochloride.

-   (xiv)    (1s,3S)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-((R)-3-fluoropiperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3S)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-((R)-3-fluoropiperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that(R)-3-fluoropiperidine was used instead of 1,4-oxazepane hydrochloride.

-   (xv)    (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-fluoropiperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-fluoropiperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that 4-fluoropiperidinewas used instead of 1,4-oxazepane hydrochloride.

-   (xvi)    (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-fluoropiperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-fluoropiperidin-l1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that(1R,4S)-2-azabicyclo[2.2.1]heptane hydrochloride was used instead of1,4-oxazepane hydrochloride.

-   (xvii)    (1s,3s)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that3-azabicyclo[4.1.0]heptane hydrochloride and6-bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewere used instead of 1,4-oxazepane hydrochloride and6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one,respectively.

-   (xviii)    (1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that 5-azaspiro[2.5]octanehydrochloride and6-bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewere used instead of 1,4-oxazepane hydrochloride and6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one,respectively.

-   (xix)    (1s,3s)-3-(6-bromo-4-(difluoromethyl)-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-bromo-4-(difluoromethyl)-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that6-bromo-4-(difluoromethyl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-onewas used instead of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xx)    (1s,3s)-3-(6′-bromo-2′-oxospiro[cyclopropane-1,3′-indolin]-1′-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6′-bromo-2′-oxospiro[cyclopropane-1,3′-indolin]-1′-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that6′-bromo-1′-(3-oxocyclobutyl)spiro[cyclopropane-1,3′-indolin]-2′-one wasused instead of6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xxi)    (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrilewas prepared using a similar procedure except that the reaction wascarried out with 5-azaspiro[2.5]octan-8-ol hydrochloride at 40° C.instead of 1,4-oxazepane hydrochloride at room temperature.

D. Preparation of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-fluoro-5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrile

In a 25 mL flask was placed3-(6-bromo-3,3-dimethyl-2-oxo-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-hydroxy-5-azaspiro[2.5]octan-5-yl)cyclobutanecarbonitrile(0.16 g, 0.36 mmol) in DCM (2 mL). To this mixture was added(diethylamino)sulfur trifluoride (0.090 ml, 0.72 mmol) at 0° C. Afterthe mixture warmed to room temperature and stirred for 1 h, it wasquenched with sat. K₂CO₃ and extracted with DCM. The combined organiclayers were dried (Na₂SO₄), concentrated, and purified by flashchromatography (100% DCM to 100% EtOAc) to give(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-fluoro-5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrile.

E. Preparation of6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one

In a 250 mL, single neck, round bottomed flask were placed commerciallyavailable 6-bromo-1,3-dihydropyrrolo[3,2-b]pyridin-2-one (1.0 g, 4.7mmol) and N,N,N′,N′-tetramethylethylenediamine (1.4 mL, 9.0 mmol) in THF(20 mL). The mixture was cooled to −78° C., and to this was dropwiseadded a solution of n-BuLi (4.7 mL, 12 mmol, 2.5 M). The resultingreaction mixture was warmed to room temperature and stirred for 18 h.Then, it was quenched with sat. NH₄Cl and extracted with DCM. Thecombined organic layers were dried (Na₂SO₄), concentrated, and purifiedby flash chromatography (100% Hexane to 100% EtOAc) to give6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one.

F. Preparation of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

In a round bottomed, single neck, 500 mL flask were placed(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile(5.0 g, 12 mmol) and AgOTf (5.1 g, 20 mmol) in THF (100 ml) undernitrogen. The mixture was stirred at room temperature for 10 min andthen it was cooled to −78° C. To this was dropwise added MeMgBr (12 mL,3.0 M in ether). Then it was immediately warmed to −10° C. Afterstirring at −10° C. for 15 min, the reaction mixture was quenched withsat. NH₄Cl and sat. NaHCO₃ and extracted with DCM. The combined organiclayers were dried (Na₂SO₄), filtered, concentrated, and purified byflash chromatography (100% DCM to 100% EtOAc) to afford6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

The following compounds were prepared using a similar procedure.

-   (i)    6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridinewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (ii)    6-Bromo-1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that EtMgBr was usedinstead of MeMgBr.

-   (iii)    6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(1,4-oxazepan-4-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (iv)    6′-Bromo-1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one

6′-Bromo-1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-onewas prepared using a similar procedure except that(1s,3s)-3-(6′-bromo-2′-oxo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (v)    1-((1s,3s)-3-(2-Oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (vi)    6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (vii)    6-Bromo-1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-fluoro-5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (viii)    1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(3-azabicyclo[3.2.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (ix)    1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (x)    6-Bromo-1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(2,2-dimethylmorpholino)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xi) 6-Bromo-3,3-dimethyl-1-((1    S,3s)-3-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-3,3-dimethyl-1-((1 S,3 s)-3-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3S)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xii)    1-((1s,3s)-3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xiii)    6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-morpholinocyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xiv) 6-Bromo-1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-1-((1 S,3s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3S)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-((R)-3-fluoropiperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xv)    6-Bromo-1-((1s,3s)-3-(4-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-1-((1s,3s)-3-(4-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-fluoropiperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xvi)    1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xvii)    1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xviii)    1-((1s,3s)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(6-oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xix)    6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xx)    1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(azepan-1-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xxi)    1-((1s,3s)-3-(3-Azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(3-Azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(3-azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xxii) 1-((1 S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1 S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3S)-1-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xxiii)    1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xxiv)    6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xxv)    6-Bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-Bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that(1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

-   (xxvi)    6-bromo-4-(difluoromethyl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

6-bromo-4-(difluoromethyl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-onewas prepared using a similar procedure except that(11s,3s)-3-(6-bromo-4-(difluoromethyl)-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(11s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1l-yl)cyclobutane-1-carbonitrile.

-   (xxvii)    6′-bromo-1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared using a similar procedure except that(1s,3s)-3-(6′-bromo-2′-oxospiro[cyclopropane-1,3′-indolin]-1′-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrilewas used instead of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.

G. Preparation of 6-bromo-4-(hydroxymethyl)-3,3-dimethylindolin-2-one

In a round bottomed, single neck, 100 mL flask was placed methyl6-bromo-3,3-dimethyl-2-oxo-indoline-4-carboxylate (2.6 g, 8.7 mmol) inMeOH (17 mL). To this was added NaBH₄ (3.4 g, 88 mmol) and the resultingmixture was heated at 50° C. for 18 h. Then it was cooled to RT,concentrated, and diluted with DCM and water. The organic layer waswashed with brine, dried (Na₂SO₄), filtered, concentrated, and used inthe next step without purification.

H. Preparation of 6-bromo-3,3-dimethyl-2-oxoindoline-4-carbaldehyde

In a round bottomed, single neck, 100 mL flask was placed6-bromo-4-(hydroxymethyl)-3,3-dimethyl-indolin-2-one (1.8 g, 6.6 mmol)in DCM (26 mL). To this was added Dess Martin periodinane (4.2 g, 10mmol) and the resulting mixture was stirred at RT for 18 h. Then it wasextracted with DCM and the combined organic layers were washed withbrine, dried (Na₂SO₄), filtered, concentrated, and used in the next stepwithout purification.

I. Preparation of 6-bromo-4-(difluoromethyl)-3,3-dimethylindolin-2-one

In a round bottomed, single neck, 100 mL flask was placed6-bromo-3,3-dimethyl-2-oxo-indoline-4-carbaldehyde (0.8 g, 3.0 mmol) inDCM (15 mL). To this was added Deoxo-Fluor” solution (1.0 g, 4.4 mmol)and the resulting mixture was stirred at RT for 18 h. Then it wasextracted with DCM and the combined organic layers were washed withbrine, dried (Na₂SO₄), filtered, concentrated, and purified using flashchromatography (100% Hexane to 100% EtOAc then 100% DCM to 100% MeOH) togive 6-bromo-4-(difluoromethyl)-3,3-dimethylindolin-2-one.

J. Preparation of tert-butyl 5-bromo-2-chloro-3,4-difluorobenzoate

In a 1000 mL, round bottomed, single neck flask was placed2,2,6,6-tetramethylpiperidine (10.7 mL, 63.3 mmol) in THF (300 mL). Thesolution was cooled to −78° C., and to this was dropwise added n-BuLi(25 mL, 63 mmol, 2.5 M in hexanes). The resulting reaction mixture wasstirred at −78° C. for 15 min. To this was dropwise added a solution of3-bromo-4,5-difluorobenzoic acid (6.00 g, 25.3 mmol) in THF (50 mL) at−78 C. The mixture was stirred at −78 C for 30 min, after whichhexachloroethane (30.0 g, 126 mmol) in 50 mL THF was added dropwise. Themixture was warmed to room temperature and stirred for 18 h. It wasquenched with H₂O, concentrated, re-dissolved in H₂O, and washed withhexanes. The aqueous layer was acidified with conc. HCl. The solids werecollected by filtration, dissolved in EtOAc, dried (Na₂SO₄),concentrated, and re-dissolved in THF (100 mL). To this were added Boc₂O(12.2 g, 55.7 mmol) and DMAP (620 mg, 5.1 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 18 h. Then, it wasconcentrated and purified by flash column chromatography (10% EtOAc inHexane to 25% EtOAc in Hexane) to give tert-butyl5-bromo-2-chloro-3,4-difluorobenzoate.

K. Preparation of 5-amino-2-chloro-3,4-difluorobenzoic acidhydrochloride

In a 500 mL, single neck, round bottomed flask were placed tert-butyl5-bromo-2-chloro-3,4-difluorobenzoate (4.75 g, 14.5 mmol), Pd₂(dba)₃(664 mg, 0.725 mmol), Xantphos (839 mg, 1.45 mmol), Cs₂CO₃ (7.09 g, 21.8mmol), and BocNH₂ (2.04 g, 17.4 mmol) in dioxane (50 mL). The reactionmixture was purged with nitrogen and stirred at 100° C. for 18 h. Thenit was cooled to room temperature, filtered through a pad of Celite,washed with DCM, and concentrated. The residue was washed through asilica column (10% EtOAc in Hexane to 100% EtOAc), concentrated, anddissolved in dioxane (15 mL). To this was added HCl (73.0 mL, 289 mmol,4.0 M in dioxane), and the resulting mixture was stirred at 55° C. for 5h. Then, it was cooled to 0° C. and the resulting precipitate wascollected by filtration to give 5-amino-2-chloro-3,4-difluorobenzoicacid hydrochloride. This compound was used without any furtherpurification.

L. Preparation of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid

In a 250 mL, single neck, round bottomed flask equipped with a refluxcondenser was placed 5-amino-2-chloro-3,4-difluorobenzoic acidhydrochloride (4.10 g, 16.8 mmol) in DMF (17 mL). The mixture was cooledto 0° C., and to this was added NaH (2.67 g, 67.2 mmol, 60% dispersionin mineral oil). The resulting mixture was stirred at 0° C. for 5 minfollowed by the addition of6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (5.07 g, 18.5mmol). After the reaction mixture was stirred at 60° C. for 30 min, itwas cooled to room temperature and was quenched with an aqueous solutionof citric acid. The precipitates were collected by filtration, washedwith H₂O, and dried under vacuum to give5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid. This compound was used without any further purification.

The following compounds were prepared using a similar procedure.

-   (i)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoic    acid

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoicacid was prepared using a similar procedure except that commerciallyavailable 5-amino-2-chloro-4-fluorobenzoic acid was used instead of5-amino-2-chloro-3,4-difluorobenzoic acid hydrochloride.

-   (ii)    3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoic    acid

3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoicacid was prepared using a similar procedure except that commerciallyavailable 3-amino-4-fluorobenzoic acid was used instead of5-amino-2-chloro-3,4-difluorobenzoic acid hydrochloride.

M. Preparation of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide

In a 250 mL, single neck, round bottomed flask were placed5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid (1.50 g, 3.37 mmol), 1-(difluoromethyl)cyclopropan-1-aminehydrochloride (0.725 g, 5.05 mmol), and HATU (2.30 g, 6.06 mmol) in DMF(15 mL). To this was added N(iPr)₂Et (2.93 mL, 16.8 mmol) at roomtemperature, and the resulting mixture was stirred at 60° C. for 1 h.The mixture was cooled to room temperature and quenched with H₂O. Theprecipitates were collected by filtration, washed with H₂O and thenEt₂O, and dried under vacuum to give5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide.This compound was used without any further purification.

The following compounds were prepared using a similar procedure.

-   (i)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoicacid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid.

-   (ii)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid.

-   (iii)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid and 1-(fluoromethyl)cyclopropan-1-amine hydrochloride were usedinstead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (iv)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid and 2,2-difluoroethan-1-amine were used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (v)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropyl-2-methylbenzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropyl-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid and propan-2-amine were used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (vi)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-cyclopropyl-3,4-difluoro-2-methylbenzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-cyclopropyl-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid and cyclopropanamine were used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (vii)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid and ethylamine were used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (viii)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(trifluoromethyl)cyclopropyl)benzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(trifluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that commerciallyavailable 1-(trifluoromethyl)cyclopropan-1-amine hydrochloride was usedinstead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (ix)    5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that1-(fluoromethyl)cyclopropan-1-amine hydrochloride was used instead of1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (x)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that2,2-difluoroethan-1-amine hydrochloride was used instead of1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (xi)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-cyclopropyl-3,4-difluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-cyclopropyl-3,4-difluorobenzamidewas prepared using a similar procedure except that cyclopropanaminehydrochloride was used instead of instead of1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (xii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewas prepared using a similar procedure except that ethylaminehydrochloride was used instead of instead of1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (xiii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-methylbenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-methylbenzamidewas prepared using a similar procedure except that methylaminehydrochloride was used instead of instead of1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (xiv)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-isopropylbenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-isopropylbenzamidewas prepared using a similar procedure except that isopropylaminehydrochloride was used instead of instead of1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (xv)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-4-fluoro-2-methylbenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that2,2-difluoroethan-1-amine hydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid were used instead of 1-(difluoromethyl)cyclopropan-1-aminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid, respectively.

-   (xvi)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that ethylaminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoicacid were used instead of 1-(difluoromethyl)cyclopropan-1-aminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid, respectively.

-   (xvii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-4-fluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-4-fluorobenzamidewas prepared using a similar procedure except that2,2-difluoroethan-1-amine hydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoicacid were used instead of 1-(difluoromethyl)cyclopropan-1-aminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid, respectively.

-   (xviii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-4-fluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-4-fluorobenzamidewas prepared using a similar procedure except that ethylaminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoicacid were used instead of 1-(difluoromethyl)cyclopropan-1-aminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid, respectively.

-   (xix)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that1-(fluoromethyl)cyclopropan-1-amine hydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoicacid were used instead of 1-(difluoromethyl)cyclopropan-1-aminehydrochloride and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid, respectively.

-   (xx)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-3-methylbenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-3-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-3-methylbenzoicacid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid.

-   (xxi)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-2,3,4-trifluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-2,3,4-trifluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoicacid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid.

-   (xxii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4-trifluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4-trifluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoicacid and ethylamine hydrochloride was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride,respectively.

-   (xxiii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-2,3,4-trifluorobenzamide

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-2,3,4-trifluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoicacid and 2,2-difluoroethan-1-amine hydrochloride was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride,respectively.

-   (xxiv)    3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamide

3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl) cyclopropyl)-4-fluorobenzamide was prepared using asimilar procedure except that3-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoicacid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid.

-   (xxv)    3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamide

3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamidewas prepared using a similar procedure except that3-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoicacid and ethylamine were used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

-   (xxvi)    3-Bromo-N-(1-(difluoromethyl)cyclopropyl)-4,5-difluorobenzamide

3-Bromo-N-(1-(difluoromethyl)cyclopropyl)-4,5-difluorobenzamide wasprepared using a similar procedure except that3-bromo-4,5-difluorobenzoic acid was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoicacid.

N. Preparation of 5-bromo-3,4-difluoro-2-methylbenzoic acid

In a 1 L, round bottomed, single neck flask was placed2,2,6,6-tetramethylpiperidine (10.7 mL, 63.3 mmol) in THF (30 mL). Thesolution was cooled to 0° C. under a nitrogen atmosphere, and to thiswas dropwise added n-BuLi (24.3 mL, 60.8 mmol, 2.5 M in hexane). Afterstirring at 0° C. for 15 min, it was dropwise added to a stirringsolution of 3-bromo-4,5-difluorobenzoic acid (6.00 g, 25.3 mmol) in THF(300 mL) at −78° C. under a nitrogen atmosphere. The mixture was stirredat −78° C. for 30 min. To this solution was dropwise added iodomethane(7.89 mL, 127 mmol) at −78° C. The resulting reaction mixture was slowlywarmed to room temperature and stirred for 18 h. It was quenched withH₂O, acidified with 2 M HCl, and extracted with EtOAc. The combinedorganic layers were washed with water, dried (Na₂SO₄), and concentratedunder vacuum to afford 5-bromo-3,4-difluoro-2-methylbenzoic acid, whichwas carried on to the subsequent reaction without further purification.

O. Preparation of tert-butyl 5-bromo-3,4-difluoro-2-methylbenzoate

In a 250 mL, single neck, round bottomed flask were placed5-bromo-3,4-difluoro-2-methylbenzoic acid (5.00 g, 19.9 mmol) and4-(dimethylamino)pyridine (730 mg, 5.98 mmol) in DCM (40 mL) and t-BuOH(40 mL). To this was added di-tert-butyl dicarbonate (8.69 g, 39.8mmol). After the reaction mixture was stirred at room temperature for 18h, it was concentrated under vacuum. The resulting crude product wasdissolved in EtOAc, washed with 10% aqueous citric acid and brine, dried(Na₂SO₄), concentrated, and purified by flash chromatography (100%Hexane to 5% EtOAc in Hexane) to afford tert-butyl5-bromo-3,4-difluoro-2-methylbenzoate.

P. Preparation of tert-butyl5-((tert-butoxycarbonyl)amino)-3,4-difluoro-2-methylbenzoate

In a sealed tube were placed tert-butyl5-bromo-3,4-difluoro-2-methylbenzoate (4.86 g, 15.8 mmol), tert-butylcarbamate (7.42 g, 63.3 mmol), Pd₂(dba)₃*CHCl₃ (724 mg, 791 umol),Xantphos (916 mg, 1.58 mmol), and Cs₂CO₃ (7.73 g, 23.7 mmol) in dioxane(67 mL). The reaction mixture was purged with nitrogen and stirred at100° C. for 3 h. Then, it was cooled to room temperature, diluted withEtOAc, and filtered through a pad of Celite. The filtrate wasconcentrated and purified by flash chromatography (100% Hexane to 30%EtOAc in Hexane) to afford tert-butyl5-((tert-butoxycarbonyl)amino)-3,4-difluoro-2-methylbenzoate.

Q. Preparation of 5-amino-3,4-difluoro-2-methylbenzoic acid

In a 100 mL, single neck, round bottomed flask was placed tert-butyl5-((tert-butoxycarbonyl)amino)-3,4-difluoro-2-methylbenzoate (3.29 g,9.58 mmol) in dioxane (20 mL). To this was added HCl (24.0 mL, 96.0mmol, 4 M in dioxane), and the resulting reaction mixture was stirred atroom temperature for 18 h. Then, it was cooled to 0° C., and theprecipitates were collected by filtration and washed with cold dioxaneto afford 5-amino-3,4-difluoro-2-methylbenzoic acid hydrochloride. Thiscompound was used without any further purification.

R. Preparation of 2-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid

In a 100 mL, single neck, round bottomed flask was placed2-chloro-4-fluoro-3-methylbenzoic acid (2.0 g, 11 mmol) in conc.sulfuric acid (20 mL). To this was drop-wise added 69% HNO₃ (0.69 mL) at0° C. The resulting mixture was warmed to RT and stirred for 3 h. Then,it was poured into the flask containing 300 mL of ice water. Theresulting precipitates were collected by filtration, washed with water,and dried to give 2-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid.

S. Preparation of 5-amino-2-chloro-4-fluoro-3-methylbenzoic acid

In a 100 mL, single neck, round bottomed flask were placed2-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid (1.0 g, 4.3 mmol) and 10wt % Pd/C (0.22 g, 0.21 mmol) in THF (10 mL). The mixture was purgedwith N₂ for 10 min, purged with H₂, and then charged with a balloonfilled with H₂. To this was added HCl in dioxane (2.2 mL, 4 M). Themixture was stirred at RT for 16 h, solubilized with MeOH, filteredthrough a pad of Celite, concentrated, re-suspended in dioxane. Theresulting solids were collected by filtration to give5-amino-2-chloro-4-fluoro-3-methylbenzoic acid.

T. Preparation of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid

In a 100 mL, single neck, round bottomed flask equipped with a refluxcondenser was placed 5-amino-3,4-difluoro-2-methylbenzoic acidhydrochloride (1.17 g, 5.23 mmol) in NMP (12 mL). The mixture was cooledto 0° C., and to this was added NaH (0.837 g, 20.9 mmol, 60% dispersionin mineral oil). The resulting mixture was stirred at room temperaturefor 15 min followed by the addition of6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (1.62 g, 6.28mmol). After the reaction mixture was stirred at 60° C. for 18 h, it wascooled to room temperature and was quenched with an aqueous solution ofcitric acid. The precipitates were collected by filtration, washed withH₂O, and dried under vacuum to give5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoicacid. This compound was used without any further purification.

The following compounds were prepared using a similar procedure.

-   (i)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-3-methylbenzoic    acid

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-3-methylbenzoicacid was prepared using a similar procedure except that5-amino-2-chloro-4-fluoro-3-methylbenzoic acid was used instead of5-amino-3,4-difluoro-2-methylbenzoic acid.

-   (ii)    5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoic    acid

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoicacid was prepared using a similar procedure except that5-amino-2,3,4-trifluorobenzoic acid was used instead of5-amino-3,4-difluoro-2-methylbenzoic acid.

U. Preparation ofN-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide(Example 185)

In a microwave vial were placed6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one(120 mg, 0.31 mmol), bis(pinacolato)diboron (93.2 mg, 0.37 mmol),Pd(PPh₃)₄ (35.3 mg, 0.03 mmol), and KOAc (90.1 mg, 0.92 mmol). Themixture was sonicated and degassed with N₂, placed in the microwavereactor, heated at 150° C. for 45 min, and cooled to RT. To this mixturewere added5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide(157 mg, 0.31 mmol) and 2M Na₂CO₃ (0.31 mL). The mixture was placed inthe microwave reactor, heated at 125° C. for 25 min, and cooled to RT.Then it was purified by flash chromatography (100% DCM to 100% MeOH)followed by reverse phase chromatography (0.1% TFA in Water/0.1% TFA inACN) to giveN-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide.

The following compounds were prepared using a similar procedure.

-   (i)    5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)    cyclopropyl)-2-methylbenzamide (Example 186)

5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (ii)    N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 187)

N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (iii)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 188)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (iv) N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1S,3    s)-3-methyl-3-((3    aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 189)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1S,3s)-3-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1 S,3s)-3-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (v)    5-((6-(1-((1s,3s)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide    (Example 190)

5-((6-(1-((1s,3s)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(6-oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

Chiral Resolution:

Separation of the isomers of5-((6-(1-((1s,3s)-3-(6-oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

5-((6-(1-((1s,3s)-3-(6-oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas separated on CHIRALPAK IA SFC 5 um 21×250 mm column in 35% MeOH(modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the two singleisomers which were further purified by reverse phase chromatography(0.1% TFA in Water/0.1% TFA in ACN):

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(6-oxa-2-CHIRALPAK IA 1^(st) eluting Example azabicyclo[3.2.1]octan- SFC 5 umpeak 191 2-yl)-3-methylcyclobutyl)- 21 × 250 mm 2^(nd) eluting Example3,3-dimethyl-2- column in peak 192 oxo-2,3-dihydro- 35% MeOH1H-pyrrolo[3,2-b] (modified with 10 pyridin-6-yl)-3- mM NH₃)/CO₂ atisopropyl-3H- 60 mL/min imidazo[4,5-c]pyridin- 4-yl)amino)-N-(1-(difluoromethyl) cyclopropyl)- 3,4-difluoro-2- methylbenzamide

-   (vi)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 193)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (vii)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 194)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (viii)    N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 195)

N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (ix) N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1 S,3    s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 196)

N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that 6-bromo-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (x)    N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1s,3s)-3-(4-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 197)

N-(1-(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1s,3s)-3-(4-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-1-((s,3s)-3-(4-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xi)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 198)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xii)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 199)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-2-oxo-2,3-dihydro-H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xiii)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1    S,3    s)-3-((R)-3-fluoropyrrolidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 200)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that 6-bromo-1-((1 S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xiv)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1    S,3    s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 201)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure (Example 185) except that6-bromo-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xv)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide    (Example 202)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xvi)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 203)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xvii)    2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(trifluoromethyl)cyclopropyl)benzamide    (Example 204)

2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(trifluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(trifluoromethyl)cyclopropyl)benzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xviii)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide    (Example 205)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xix)    N-(1-(Difluoromethyl)cyclopropyl)-4-fluoro-5-((3-isopropyl-6-(1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2′-oxo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-6′-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 206)

N-(1-(Difluoromethyl)cyclopropyl)-4-fluoro-5-((3-isopropyl-6-(1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2′-oxo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-6′-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6′-bromo-1′-((s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xx)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 207)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrol[32-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure (Example 185) except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxi)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 208)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xxii)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide    (Example 209)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xxiii)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((3-isopropyl-6-(1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2′-oxo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-6′-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 210)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((3-isopropyl-6-(1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2′-oxo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-6′-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that6′-bromo-1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxiv)    2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide    (Example 211)

2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxv)    5-((6-(1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide    (Example 212)

5-((6-(1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxvi)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide    (Example 213)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxvii)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 214)

N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridinewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xxviii)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide    (Example 215)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1r, 3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxix)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide    (Example 216)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxx)    N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 217)

N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxi)    N-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide    (Example 218)

N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that3-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxii)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide    (Example 219)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridineand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxiii)    5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropyl-2-methylbenzamide    (Example 220)

5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropyl-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropyl-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxiv)    N-Cyclopropyl-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 221)

N-Cyclopropyl-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-cyclopropyl-3,4-difluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxv)    5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide    (Example 222)

5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxvi)    3-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamide    (Example 223)

3-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamidewas prepared using a similar procedure except that3-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (xxxvii) 2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dim    ethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 245)

2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xxxviii)    N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 246)

N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (xxxix)    6-(4-Amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

V. Preparation of5-((6-(1-((1s,3s)-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide(Example 224)

In a sealed tube were placed6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one(150 mg, 0.36 mmol), bis(pinacolato)diboron (109 mg, 0.43 mmol),Pd(PPh₃)₄ (80.0 mg, 0.07 mmol), and KOAc (105 mg, 1.07 mmol) in dioxane(1 ml) under nitrogen. After stirring at 140° C. for 1 h, the mixturewas to room temperature. To this were added5-[(6-bromo-3-isopropyl-imidazo[4,5-c]pyridin-4-yl)amino]-N-[1-(difluoromethyl)cyclopropyl]-3,4-difluoro-2-methyl-benzamide(184 mg, 0.36 mmol) and 2M Na₂CO₃ (0.89 mL, 1.78 mmol). The resultingmixture was heated at 90° C. for 1 h, and then it was quenched withwater. The mixture was extracted with EtOAc, concentrated, and purifiedby flash chromatography (100% DCM to 100% MeOH in DCM) and reverse phasechromatography (0.1% TFA in Water/0.1% TFA in ACN) to give5-((6-(1-((1s,3s)-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

The following compounds were prepared using a similar procedure.

-   (i)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide    (Example 225)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide were used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (ii)    5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide    (Example 226)

5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (iii)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide    (Example 227)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (iv)    5-((6-(1-((1s,3s)-3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide    (Example 228)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (v)    5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide    (Example 229)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (vi)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)    cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 230)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

-   (vii)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide    (Example 231)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

Chiral Separation: Separation of the isomers of5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide(Example 231)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas separated on CHIRALPAK IA SFC 5 um 21×250 mm column in 35% MeOH(modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the two singleisomers which were further purified by reverse chromatography (0.1% TFAin Water/0.1% TFA in ACN):

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(3-CHIRALPAK IA SFC 1^(st) Example 232 azabicyclo[4.1.0]heptan-3-yl)-3- 5um 21 × 250 mm eluting peak methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-column in 35% MeOH 2^(nd) Example 233dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3- (modified with 10 mM elutingpeak isopropyl-3H-imidazo[4,5-c]pyridin-4- NH₃)/CO₂ atyl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4- 60 mL/mindifluoro-2-methylbenzamide

-   (viii)    5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide    (Example 234)

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

-   (ix)    5-((6-(1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamide    (Example 247)

5-((6-(1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (x)    5-((6-(1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamide    (Example 248)

5-((6-(1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xi)    5-((6-(1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide    (Example 249)

5-((6-(1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xii)    2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 250)

2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xiii) 5-((6-(1-((1    s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamide    (Example 251)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

Chiral Separation: Separation of the isomers of5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamide(Example 251)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewas separated on CHIRALPAK IA SFC 5 um 21×250 mm column in 35% MeOH(modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the two singleisomers which were further purified by reverse chromatography (0.1% TFAin Water/0.1% TFA in ACN):

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(3-CHIRALPAK IA SFC 1^(st) 252 azabicyclo[4.1.0]heptan-3-yl)-3- 5 um 21 ×250 mm eluting peak methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3- column in35% MeOH 2^(nd) 253 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3- (modifiedwith 10 mM eluting peak isopropyl-3H-imidazo[4,5-c]pyridin-4- NH₃)/CO₂at yl)amino)-2-chloro-N-ethyl-3,4- 60 mL/min difluorobenzamide

-   (xiv)    5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-isopropylbenzamide    (Example 254)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-isopropylbenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-isopropylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xv)    5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide    (Example 255)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xvi)    5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamide    (Example 256)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

-   (xvii)    5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide    (Example 257)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

Chiral Separation: Separation of the isomers of5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide(Example 257)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas separated on CHIRALPAK IA SFC 5 um 21×250 mm column in 35% MeOH(modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the two singleisomers which were further purified by reverse chromatography (0.1% TFAin Water/0.1% TFA in ACN):

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(3-CHIRALPAK IA SFC 1^(st) 258 azabicyclo[4.1.0]heptan-3-yl)-3- 5 um 21 ×250 mm eluting peak methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3- column in35% MeOH 2^(nd) 259 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3- (modifiedwith 10 mM eluting peak isopropyl-3H-imidazo[4,5-c]pyridin-4- NH₃)/CO₂at yl)amino)-2-chloro-3,4-difluoro-N-(1- 60 mL/min(fluoromethyl)cyclopropyl)benzamide

-   (xviii)    5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide    (Example 260)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide,respectively.

Chiral Separation: Separation of the isomers of5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide(Example 260)

5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas separated on CHIRALPAK IA SFC 5 um 21×250 mm column in 35% MeOH(modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the two singleisomers which were further purified by reverse chromatography (0.1% TFAin Water/0.1% TFA in ACN):

Name Separation method Peak # Example # 5-((6-(1-((1s,3s)-3-(3-CHIRALPAK IA SFC 1^(st) 261 azabicyclo[4.1.0]heptan-3-yl)-3- 5 um 21 ×250 mm eluting peak methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3- column in35% MeOH 2^(nd) 262 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3- (modifiedwith 10 mM eluting peak isopropyl-3H-imidazo[4,5-c]pyridin-4- NH₃)/CO₂at yl)amino)-2-chloro-N-(1- 60 mL/min (difluoromethyl)cyclopropyl)-3,4-difluorobenzamide

-   (ix)    6-(4-Amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

6-(4-Amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-onewas prepared using a similar procedure except that6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine was used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

W. Preparation of 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one

In a 500 mL, single neck, round bottomed flask were placed6-bromo-3,3-dimethylindolin-2-one (5.0 g, 20.8 mmol) and Cs₂CO₃ (20.4 g,62.5 mmol) in NMP (80 mL). To this was dropwise added3-bromocyclobutan-1-one (4.7 g, 31.2 mmol) under nitrogen. After themixture was stirred at room temperature for 1.5 h, it was quenched withwater and extracted with EtOAc. The combined organic layers were washedwith water, brine, dried (Na₂SO₄), concentrated, and purified by flashchromatography to give6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one.

X. Preparation of(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile

In a 250 mL, single neck, round bottomed flask was placed6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one (4.0 g, 12.9 mmol)in AcOH (22 mL), and the mixture was cooled to 0° C. To this wasdropwise added piperidine (2.2. g, 25.9 mmol) followed by theportion-wise addition of TMS-CN (2.9 g, 29.8 mmol). The reaction mixturewas warmed to room temperature and stirred for 18 h. Then, it wasconcentrated, quenched with sat. NaHCO₃, and extracted with DCM. Thecombined organic layers were washed with water and brine, dried(Na₂SO₄), and concentrated. The residue was re-suspended in EtOAc andstirred at room temperature for 10 minutes. The solid was collected byfiltration, washed with EtOAc, and dried to give(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile.This compound was used without any further purification.

Y. Preparation of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

In a 250 mL, single neck, round bottomed flask were placed silvertriflate (352.5 mg, 1.4 mmol) and(1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutane-1-carbonitrile(345.0 mg, 0.9 mmol) in THF (9 mL). The mixture was stirred at roomtemperature for 5 minutes, and cooled to −78° C. To this was drop wiseadded MeMgBr (1.0 mL, 3.4 mmol, 3.0 M in ether). The resulting mixturewas stirred at −78° C. for 45 minutes, quenched with water, andextracted with EtOAc. Combined organic layers were washed with water,brine, dried (Na₂SO₄), concentrated, and purified by flashchromatography (100% Hexane to 100% EtOAc) to give6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

Z. Preparation ofN-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide(Example 235)

In a 100 mL, single neck, round bottomed flask were placed6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one(145.0 mg, 0.4 mmol), bispinacolato diboron (112.9 mg, 0.4 mmol),potassium acetate (109.1 mg, 1.1 mmol) and Pd(dppf)Cl₂-DCM adduct (42.8mg, 0.04 mmol) in dioxane (3 mL) under nitrogen. The mixture was stirredat 90° C. for 18 h. Then it was cooled to room temperature, diluted withEtOAc, and filtered through a pad of Celite. The filtrate was washedwith water, brine, dried (Na₂SO₄) and concentrated. To this residue wereadded5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide(91.0 mg, 0.2 mmol), Pd(PPh₃)₄ (21.1 mg, 0.02 mmol), and 2M Cs₂CO₃ (0.46mL, 0.9 mmol) in DME (2 mL) under nitrogen. After stirring at 100° C.for 2 h, the mixture was cooled to room temperature and filtered througha pad of Celite. The filtrate was concentrated and purified by flashchromatography (10% NH₄OH/MeOH/EtOAc/Hexane) followed by reverse phasechromatography (0.1% TFA in Water/0.1% in ACN) to giveN-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide.

The following compounds were prepared using a similar procedure.

-   (i)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 236)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (ii)    N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 237)

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolineand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (iii)    N-(1-(Difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide    (Example 238)

N-(1-(Difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamidewas prepared using a similar procedure except that3-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (iv)    5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide    (Example 239)

5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (v)    3-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamide    (Example 240)

3-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamidewas prepared using a similar procedure except that3-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (vi)    2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 241)

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (vii) 5-((6-(1-((1 S,3    s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide    (Example 263)

5-((6-(1-((1 S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas prepared using a similar procedure except that 1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (viii)    2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-3-methylbenzamide    (Example 264)

2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrol[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-3-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-3-methylbenzamideinstead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (ix)    2-chloro-N-cyclopropyl-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 265)

2-chloro-N-cyclopropyl-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-cyclopropyl-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (x)    N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide    (Example 266)

N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-4-fluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xi)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropylbenzamide    (Example 267)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-isopropylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xii)    N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 268)

N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xiii)    N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 269)

N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrol[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xiv)    2-chloro-N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 270)

2-chloro-N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xv)    N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 271)

N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xvi)    2-chloro-N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 272)

2-chloro-N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewere used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xvii)    2-chloro-N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 273)

2-chloro-N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrol[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xviii)    N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzamide    (Example 274)

N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-2,3,4-trifluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xix)    2-chloro-N-(2,2-difluoroethyl)-3,4-difluoro-5-((3-isopropyl-6-(1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 275)

2-chloro-N-(2,2-difluoroethyl)-3,4-difluoro-5-((3-isopropyl-6-(1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that6′-bromo-1′-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)spiro[cyclopropane-1,3′-indolin]-2′-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewere used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xx)    5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamide    (Example 276)

5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxi)    N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 277)

N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxii) 5-((6-(3,3-dimethyl-1-((1    s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4-trifluorobenzamide    (Example 278)

5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4-trifluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4-trifluorobenzamidewere used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxiii)    N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide    (Example 279)

N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxiv)    N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzamide    (Example 280)

N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-2,3,4-trifluorobenzamidewere used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxv)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-methylbenzamide    (Example 281)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxvi)    2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 282)

2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxvii)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluorobenzamide    (Example 283)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamideinstead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxviii)    N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide    (Example 284)

N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxix)    5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide    (Example 285)

5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxx)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluorobenzamide    (Example 286)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluorobenzamidewas prepared using a similar procedure except that6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxxi)    2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide    (Example 287)

2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxxii)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluorobenzamide    (Example 288)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxxiii)    2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide    (Example 289)

2-chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxxiv)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamide    (Example 290)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxxv)    2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide    (Example 291)

2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamidewas prepared using a similar procedure except that6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

-   (xxxvi)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide    (Example 292)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxxvii)    2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide    (Example 293)

2-chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)benzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

-   (xxxviii)    2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide    (Example 294)

2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamidewas prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

AA. Preparation of6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

In a 100 mL, single neck, round bottomed flask were placed6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (250 mg,1.04 mmol), DMAP (13.0 mg, 0.10 mmol), and Boc₂O (294 mg, 1.35 mmol) inTHF (5 mL). After stirring at room temperature for 18 hrs, the mixturewas concentrated and purified by flash column chromatography (100%Hexane to 100% EtOAc) to give tert-butyl6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylatewhich was dissolved in MeCN (dried over sieves, 10 mL). To this wasadded AgF2 (438 mg, 3.0 mmol), and the resulting reaction mixture wasstirred at 40° C. for 18 h. Then, the reaction mixture was cooled toroom temperature and filtered through a pad of Celite. The filtrate wasconcentrated and purified by flash column chromatography (100% Hexane to100% EtOAc) to give tert-butyl6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylatewhich was dissolved in DCM (3 mL). To this was added TFA (0.45 mL, 5.93mmol). After stirring at room temperature for 30 min, the reactionmixture was quenched with sat. NaHCO₃ and extract with DCM. The combinedorganic layers were dried (Na₂SO₄), concentrated, and purified by flashcolumn chromatography (100% Hexanes to 100% EtOAc) to give6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

Procedure 41: Preparation of the Compounds of Formula I According toReaction Scheme IX

A. Preparation ofN-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5-difluorobenzamide(Example 242)

In a microwave vial were placed6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one(95.0 mg, 0.19 mmol),3-bromo-N-(1-(difluoromethyl)cyclopropyl)-4,5-difluorobenzamide (127 mg,0.39 mmol), Pd₂(dba)₃ (17.8 mg, 0.02 mmol), Xanthphos (20 mg, 0.04mmol), and Cs₂CO₃ (254 mg, 0.78 mmol) in Dioxane (3 mL) under nitrogen.The mixture was placed in the microwave reactor and heated at 150° C.for 45 min. Then it was purified by flash chromatography (100% DCM to100% MeOH) followed by reverse phase chromatography (0.1% TFA inWater/0.1% TFA in ACN) to giveN-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5-difluorobenzamide.

B. Preparation ofN-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5-difluorobenzamide(Example 243)

In a 100 mL, single neck, round bottomed flask were placed6-(4-amino-3-isopropyl-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-[3-methyl-3-(1-piperidyl)cyclobutyl]indolin-2-one (127 mg, 0.26 mmol),3-bromo-N-[1-(difluoromethyl)cyclopropyl]-4,5-difluoro-benzamide (170mg, 0.52 mmol), XantPhos Pd G4 (50.2 mg, 0.05 mmol), and Cesiumcarbonate (48.6 mg, 0.78 mmol) in dioxane (10 mL) under nitrogen. Afterstirring at 150° C. for 18 h, the reaction mixture was transferred to amicrowave vial, placed in the microwave reactor, and heated at 150° C.for 1 h. Then it was filtered through a pad of Celite, washed with MeOH,concentrated, and purified by flash chromatography (DCM/5% NEt3 in MeOH)and reverse phase chromatography (0.1% TFA in Water/0.1% TFA in ACN) togiveN-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5-difluorobenzamide.

Procedure 42: Preparation of the Compounds of Formula I According toReaction Scheme X

A. Preparation of methyl 2-(2-bromo-4-chlorophenyl)acetate

In a 100 mL, single neck, round bottomed flask was placed commerciallyavailable 2-(2-bromo-4-chloro-phenyl)acetic acid (5 g, 20.0 mmol) inmethanol (30 mL). To this was added H₂SO₄ (0.3 mL) and the resultingmixture was stirred at RT for 16 h. Then, it was concentrated,re-dissolved in DCM and sat. NaHCO₃, and extracted with DCM. Thecombined organic layers were washed with water and brine, dried(Na₂SO₄), purified by flash chromatography (100% Hexane to 100% EtOAc)to afford methyl 2-(2-bromo-4-chlorophenyl)acetate.

B. Preparation of methyl 2-(2-bromo-4-chlorophenyl)-2-methylpropanoate

In a 100 mL, single neck, round bottomed flask was placed methyl2-(2-bromo-4-chlorophenyl)acetate (5.0 g, 19 mmol) in THF (30 mL). Tothis was added NaH (2.3 g, 57 mmol) at 0° C. and the resulting mixturewas stirred for 20 min followed by the addition of MeI (8.1 g, 57 mmol).After the mixture was warmed to RT and stirred for 5 hr, it was quenchedwith sat. NH₄Cl and extracted with DCM. The combined organic layers werewashed with water and brine, dried (Na₂SO₄), and purified by flashchromatography (100% Hexane to 100% EtOAc) to give methyl2-(2-bromo-4-chlorophenyl)-2-methylpropanoate.

Methyl 2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoate was preparedusing a similar procedure except that commercially available methyl2-(3-bromo-5-chloropyridin-2-yl)acetate was used instead of methyl2-(2-bromo-4-chlorophenyl)acetate.

C. Preparation of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoic acid

In a 100 mL, single neck, round bottomed flask equipped with a refluxcondenser was placed methyl2-(2-bromo-4-chlorophenyl)-2-methylpropanoate (2.2 g, 7.5 mol) inmethanol (10 mL) and water (10 mL). To this was added NaOH (2 g, 50mmol) and the resulting mixture was stirred at 110° C. for 16 h. Then itwas cooled to RT, concentrated under reduced pressure, re-dissolved inwater. To this was added citric acid to lower pH to 6. The precipitateswere collected by filtration, washed with water, and dried to give2-(2-bromo-4-chlorophenyl)-2-methylpropanoic acid which was used in thenext step without further purification.

2-(3-Bromo-5-chloropyridin-2-yl)-2-methylpropanoic acid was preparedusing a similar procedure except that methyl2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoate was used instead ofmethyl 2-(2-bromo-4-chlorophenyl)-2-methylpropanoate.

D. Preparation of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoyl chloride

In a 100 mL, single neck, round bottomed flask equipped with a refluxcondenser was placed 2-(2-bromo-4-chlorophenyl)-2-methyl-propanoic acid(800 mg, 2.9 mmol). To this was added thionyl chloride (6.3 mL, 86 mmol)and DMF (0.5 mL). The resulting mixture was stirred at 80° C. for 3 h.Then it was cooled to RT and concentrated to give2-(2-bromo-4-chlorophenyl)-2-methylpropanoyl chloride which was used inthe next step without further purification.

2-(3-Bromo-5-chloropyridin-2-yl)-2-methylpropanoyl chloride was preparedusing a similar procedure except that2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoic acid was used insteadof 2-(2-bromo-4-chlorophenyl)-2-methyl-propanoic acid.

E. Preparation of tert-butyl((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate

In a 100 mL, single neck, round bottomed flask was placed2-(2-bromo-4-chlorophenyl)-2-methylpropanoyl chloride (820 mg, 2.8 mmol)in dichloromethane (10 mL). To this were added to tert-butyl((1s,3s)-3-amino-3-methylcyclobutyl)carbamate (560 mg, 2.8 mmol) andDIPEA (5 mL, 29 mmol). The resulting mixture was stirred at RT for 16 h.Then, it was quenched with water and extracted with DCM. The combinedorganic layers were washed with water and brine, dried (Na₂SO₄), andconcentrated to give tert-butyl((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamatewhich was used in the next step without purification.

tert-Butyl((1s,3s)-3-(2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanamido)-3-methylcyclobutyl)carbamatewas prepared using a similar procedure except that2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoyl chloride was usedinstead of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoyl chloride.

F. Preparation of1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one

In a 100 mL, single neck, round bottomed flask were placed tert-butyl((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate(600 mg, 1.3 mmol) and KOH (600 mg, 11 mmol) in DMSO (6 mL). After themixture was stirred at 120° C. for 16 h, it was cooled to RT, dilutedwith water, neutralized with 2 N HCl, and extracted with DCM:IPA (3:1).The combined organic layers were concentrated and purified by flashchromatography (100% DCM to 100% MeOH) to give1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one.

1-((1s,3s)-3-Amino-1-methylcyclobutyl)-6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that tert-butyl((1s,3s)-3-(2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanamido)-3-methylcyclobutyl)carbamatewas used instead of tert-butyl((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate.

G. Preparation of6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

In a 200 mL, single neck, round bottomed flask was placed1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one(40 mg 0.14 mmol) in dichloromethane (20 mL). To this was addedglutaraldehyde (120 mg, 0.86 mmol) in dichloromethane (40 mL) followedby the addition of sodium triacetoxyborohydride (91 mg, 0.43 mmol) andacetic acid (26 mg, 0.43 mmol). After the mixture was stirred at RT for3 h, it was quenched with sat. NaHCO₃ and extracted with DCM. Thecombined organic layers were washed with sat. NaHCO₃ and brine,concentrated, and purified by flash chromatography (100% DCM to 100%MeOH) to give6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

6-Chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one.

H. Preparation of3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

In a sealed tube were placed6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one(40 mg, 0.12 mmol), bis(pinacolato)diboron (88 mg, 0.35 mmol), potassiumacetate (45 mg, 0.46 mmol), Pd₂dba₃ (5.3 mg, 0.0058 mmol) and XPhos (8.3mg, 0.017 mol) in dioxane (2 mL). The mixture was sparged with nitrogenfor 5 min and stirred at 100° C. for 72 h. Then, it was cooled to RT,diluted with EtOAc, and filtered through a pad of Celite. The filtratewas concentrated to give3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-onewhich was used in the next step without purification.

3,3-Dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas prepared using a similar procedure except that6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewas used instead of6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

I. Preparation ofN-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide(Example 295)

In a sealed tube were placed3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(40 mg, 0.046 mmol),5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide(110 mg, 0.23 mmol), Pd(PPh₃)₄ (2.6 mg, 0.0023 mmol), 2 M Na₂CO₃ (0.068mL) in dioxane (4 mL). The mixture was degassed with N₂ and stirred at90° C. for 2 h. Then, it was cooed to RT, diluted with EtOAc (4 mL), andfiltered through a pad of Celite. The filtrate was concentrated andpurified by flash chromatography (100% DCM to 100% MeOH) and reversephase chromatography (0.1% TFA in ACN/0.1% TFA in water) to giveN-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide.

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide(Example 296) was prepared using a similar procedure except that5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewas used instead of5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrol[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide(Example 297) was prepared using a similar procedure except that3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamidewere used instead of3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-oneand5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide,respectively.

Analytical Data for Examples 1-297 are set forth in Table 1.

HPK1 IC₅₀ Assay

The enzymatic activity of human HPK1 (MAP4K1) was monitored in abiochemical assay in the presence or absence of compounds and using asynthetic peptide substrate. An increase in phosphorylation of thepeptide by HPK1 was indicative of its kinase activity.

Recombinant HPK1 kinase domain produced via baculovirus infection ofinsect cells was obtained from Proteros (Proteros Biostructures #PR-0322) and was pre-activated in the presence of 2 mM ATP(Sigma-Aldrich, cat # GE27-2056-01) and 2 mM magnesium chloride for 16hours at 4° C. The protein reaction mixture was then loaded to adesalting column (Thermo Fisher Scientific, Cat #89889) to remove excessATP. HPK1 was eluted with buffer containing 20 mM Tris(2-Amino-2-(hydroxymethyl)propane-1,3-diol) pH 8.0, 150 mM NaCl, 2 mMdithiothreitol and 5% glycerol, and was frozen at −80° C. for later use.HPK1 dual phosphorylation was confirmed by mass spectrometry.

Ten nanoliters of test compounds dissolved in DMSO at variousconcentrations were dispensed into a 384-well ProxiPlate (PerkinElmer#6008289). Five microliters of a solution of recombinant HPK1 diluted inHPK1 kinase assay buffer (50 mM BES[N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid], pH 7.0; 10 mMmagnesium chloride; 0.01% Triton X-100; 1 mM dithiothreitol; 0.01%bovine serum albumin; 0.1 mM sodium orthovanadate) was added to thecompound-containing plate and was incubated for 15 minutes at 25° C.Five microliters of a mixture of ATP (Sigma-Aldrich # A6559) and peptidesubstrate STK S1 (Cisbio #61ST1BLC) diluted in HPK1 kinase assay bufferwas then added to start the reaction. Final concentrations were 0.15 nMfor HPK1, 10 μM for ATP, and 1 μM for the STK S1 peptide substrate. Thereaction mixture was incubated at 25° C. for 3 hours and was stoppedwith the addition of 10 μl of an EDTA (Ethylenediaminetetraaceticacid)-containing detection buffer (Cisbio #62SDBRDF) supplemented withEuropium cryptate-labeled anti-phospho-serine/threonine antibodies(Cisbio #62ST1PEJ) and XL665-labeled streptavidin (Cisbio #610SAXLG).The mixture was incubated for 16 hours at room temperature and peptidephosphorylation was measured by time-resolved fluorescence energytransfer (665 nm/620 nm) on an Envision plate reader (PerkinElmer).

Data in Table 1 were normalized based on positive (staurosporine) andnegative (DMSO) controls. Least squares curve fittings were performedusing a four-parameter variable slope nonlinear regression model. IC₅₀is defined as the concentration of compound required to inhibit 50% ofmaximum phosphorylation. IC₅₀ values from multiple experiments wereaveraged by geometric mean and the standard deviation was calculated.

TABLE 1 Example ES/MS HPK1 IC₅₀ # m/z ¹H-NMR (nM)  1 620.4 ¹H NMR (400MHz, DMSO-d6) delta 9.42 (d, J = 9.5 0.08 Hz, 1H), 8.77 (s, 1H), 8.49(s, 1H), 8.15 (q, J = 4.5 Hz, 1H), 7.86 (s, 1H), 7.75 (dd, J = 7.8, 1.5Hz, 1H), 7.60-7.46 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.23- 7.06 (m,1H), 5.30 (p, J = 6.5 Hz, 1H), 4.34-4.08 (m, 1H), 3.43 (dd, J = 51.1,10.0 Hz, 3H), 2.97-2.65 (m, 8H), 2.30 (s, 3H), 1.82 (d, J = 14.0 Hz,2H), 1.55 (d, J = 6.5 Hz, 9H), 1.28 (s, 8H).  2 660.4 ¹H NMR (400 MHz,DMSO-d6) delta 9.35-9.25 (m, 0.1 1H), 8.66 (s, 1H), 8.54-8.38 (m, 2H),7.89 (s, 1H), 7.78 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H),7.59 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.2, 2.4 Hz, 1H), 7.38 (d, J =7.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.30 (p, J = 6.6 Hz, 1H), 4.37(hex, J = 8.2 Hz, 1H), 4.26 (p, J = 7.8 Hz, 1H), 3.49 (q, J = 8.5 Hz,1H), 3.42-3.35 (m, 2H), 2.99-2.87 (m, 2H), 26.87- 2.72 (m, 4H), 2.30 (s,3H), 2.21-2.12 (m, 2H), 2.00- 1.88 (m, 2H), 1.87-1.79 (m, 2H), 1.75-1.67(m, 1H), 1.67-1.53 (m, 10H), 1.47-1.35 (m, 1H), 1.29 (s, 6H).  3 634.4¹H NMR (400 MHz, DMSO-d6) delta 10.40-10.05 0.1 (m, 2H), 8.81 (s, 1H),8.74 (s, 1H), 8.40-8.25 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H),7.65- 7.52 (m, 2H), 5.19-5.07 (m, 1H), 4.50 (q, J = 6.5 Hz, 1H),4.44-4.30 (m, 1H), 4.04-3.46 (m, 6H), 3.28-3.09 (m, 1H), 3.09-2.90 (m,2H), 2.85-2.75 (m, 2H), 2.48-2.05 (m, 3H), 1.90-1.64 (m, 5H), 1.58-1.34(m, 9H), 1.24 (t, J = 6.5 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H).  4 624.4 ¹HNMR (400 MHz, DMSO-d6) delta 10.70-10.46 0.1 (m, 1H), 8.62 (s, 1H), 8.44(s, 1H), 8.16 (q, J = 4.6 Hz, 1H), 7.88 (s, 1H), 7.77 (dd, J = 7.8, 1.4Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.52-7.46(m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.62-5.40(m, 1H), 5.29 (p, J = 6.6 Hz, 1H), 4.35 (q, J = 8.4 Hz, 1H), 3.95-3.50(m, 6H), 3.03-2.92 (m, 2H), 2.86-2.72 (m, 6H), 2.31 (s, 3H), 1.55 (d, J= 6.4 Hz, 6H), 1.30 (s, 6H).  5 624.4 ¹H NMR (400 MHz, DMSO-d6) delta10.71-10.52 0.2 (m, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 8.17 (q, J = 4.6Hz, 1H), 7.87 (s, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.59 (d, J = 7.3Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.52-7.46 (m, 1H), 7.39 (d, J = 7.8Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.52 (d, J = 51.4 Hz, 1H), 5.31 (p, J= 6.6 Hz, 1H), 4.33 (p, J = 8.1 Hz, 1H), 3.96-3.49 (m, 3H), 3.42-3.20(m, 1H), 2.98 (q, J = 10.2 Hz, 2H), 2.86-2.72 (m, 5H), 2.60-2.05 (m, 3H,overlapped with solvent), 2.32 (s, 3H), 1.57 (d, J = 6.4 Hz, 6H), 1.30(s, 6H).  6 634.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.29-9.10 (m, 0.1 1H),8.62 (s, 1H), 8.44 (s, 1H), 8.17 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H), 7.78(dt, J = 7.8, 2.0 Hz, 1H), 7.63- 7.54 (m, 2H), 7.49-7.44 (m, 1H),7.42-7.34 (m, 1H), 7.20 (d, J = 8.4, 1H), 5.28 (p, J = 6.5 Hz, 1H),4.56-4.41 (m, 1H), 4.38-4.16 (m, 5H), 4.14-4.02 (m, 1H), 3.19-3.11 (m,1H), 2.99-2.69 (m, 7H), 2.33 (s, 3H), 2.20-1.99 (m, 1H), 1.55 (d, J =6.6 Hz, 6H), 1.30 (s, 6H).  7 654.3 ¹H NMR (400 MHz, DMSO-d6) delta11.25-10.15 0.4 (m, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 8.21-8.15 (m, 1H),7.87 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J = 2.4Hz, 1H), 7.52-7.44 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.3Hz, 1H), 5.37-5.21 (m, 1H), 4.29 (p, J = 8.2 Hz, 1H), 3.85 (s, 2H), 3.69(s, 2H), 3.14 (s, 1H), 3.04-2.85 (m, 4H), 2.81-2.70 (m, 5H), 2.32 (s,3H), 1.56 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H).  8 666.4 ¹H NMR (400 MHz,DMSO-d6) delta 9.92 (s, 1H), 0.08 8.66 (s, 1H), 8.34 (s, 1H), 8.19 (d, J= 4.7 Hz, 1H), 7.83 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.43-7.34 (m,2H), 7.20 (d, J = 12.0 Hz, 1H), 5.32-5.22 (m, 1H), 4.08 (p, J = 8.6 Hz,1H), 3.95 (s, 2H), 3.87 (d, J = 12.4 Hz, 2H), 3.72 (d, J = 12.2 Hz, 2H),3.54 (q, J = 8.2 Hz, 1H), 2.96 (q, J = 9.8, 9.2 Hz, 2H), 2.91-2.82 (m,2H), 2.73 (d, J = 4.5 Hz, 3H), 2.36 (s, 3H), 2.22- 2.13 (m, 2H),2.13-2.05 (m, 2H), 1.59 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H).  9 652.3 ¹HNMR (400 MHz, DMSO-d6) delta 10.42-9.15 0.1 (m, 1H), 8.71 (s, 1H),8.40-8.33 (m, 1H), 8.23-8.17 (m, 1H), 7.84 (s, 1H), 7.73-7.60 (m, 2H),7.43 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.23 (dd, J = 12.1, 2.9 Hz, 1H),5.29 (p, J = 6.8 Hz, 1H), 4.53-3.99 (m, 8H), 3.22-2.76 (m, 5H), 2.74 (d,J = 4.5 Hz, 3H), 2.41-2.37 (m, 3H), 2.16-2.04 (m, 1H), 1.59 (d, J = 6.6Hz, 6H), 1.29 (d, J = 1.8 Hz, 6H).  10 666.3 ¹H NMR (400 MHz, DMSO-d6)delta 9.35 (s, 1H), 0.1 8.65 (s, 1H), 8.35 (s, 1H), 8.21-8.16 (m, 1H),7.85 (s, 1H), 7.68 (dd, J = 7.9, 1.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H),7.43 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 12.1 Hz, 1H), 5.27(p, J = 6.6 Hz, 1H), 4.52 (s, 2H), 4.13 (p, J = 8.5 Hz, 1H), 3.70-3.58(m, 1H), 3.41-3.33 (m, 2H), 3.06 (t, J = 10.9 Hz, 2H), 3.00- 2.88 (m,2H), 2.79-2.69 (m, 5H), 2.38 (s, 3H), 2.04- 1.92 (m, 4H), 1.59 (d, J =6.5 Hz, 6H), 1.29 (s, 6H).  11 594.3 ¹H NMR (400 MHz, Methanol-d4) delta9.06 (s, 1H), 0.1 7.79-7.71 (m, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 (d,J = 1.4 Hz, 1H), 7.40-7.33 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 5.33 (p, J= 6.6 Hz, 1H), 4.37 (p, J = 8.2 Hz, 1H), 3.81 (p, J = 8.1 Hz, 1H), 3.39(p, J = 6.4 Hz, 1H), 2.91 (t, J = 8.0 Hz, 4H), 2.85 (s, 3H), 2.40 (s,3H), 1.68 (d, J = 6.6 Hz, 6H), 1.38-1.28 (m, 12H).  12 650.3 ¹H NMR (400MHz, Methanol-d4) delta 9.08 (s, 1H), 0.09 7.78-7.71 (m, 2H), 7.69 (d, J= 2.3 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 7.41-7.32 (m, 2H), 7.26 (d, J =8.3 Hz, 1H), 5.33 (p, J = 6.6 Hz, 1H), 4.36 (p, J = 8.2 Hz, 1H), 4.01(dd, J = 11.8, 4.8 Hz, 1H), 3.88 (p, J = 7.8 Hz, 1H), 3.76 (d, J = 11.7Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.54-3.38 (m, 2H), 2.96 (d, J = 4.0Hz, 4H), 2.85 (s, 3H), 2.40 (s, 3H), 2.10 (s, 1H), 1.94- 1.82 (m, 1H),1.77 (d, J = 12.7 Hz, 1H), 1.68 (d, J = 6.6 Hz, 6H), 1.35 (s, 6H), 1.15(d, J = 7.1 Hz, 3H).  13 650.3 ¹H NMR (400 MHz, Methanol-d4) delta 9.09(s, 1H), 0.1 7.80 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 2.3 Hz, 1H), 7.66(d, J = 1.3 Hz, 1H), 7.44-7.37 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 5.37(q, J = 6.6 Hz, 1H), 4.46 (q, J = 7.7 Hz, 1H), 4.06 (d, J = 12.3 Hz,1H), 4.03-3.88 (m, 2H), 3.54-3.42 (m, 1H), 3.15 (t, J = 11.3 Hz, 2H),3.10-2.97 (m, 3H), 2.90 (s, 4H), 2.45 (s, 3H), 2.06 (d, J = 12.4 Hz,1H), 1.94-1.81 (m, 1H), 1.73 (dd, J = 6.5, 5.2 Hz, 7H), 1.41 (s, 6H),1.11 (d, J = 6.6 Hz, 3H).  14 612.3 ¹H NMR (400 MHz, Methanol-d4) delta8.98 (s, 1H), 0.3 7.88 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.72 (dd, J =7.8, 1.5 Hz, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H),7.17 (d, J = 11.7 Hz, 1H), 5.33 (p, J = 6.5 Hz, 1H), 4.32 (q, J = 8.1Hz, 1H), 3.85 (t, J = 7.8 Hz, 1H), 3.43 (p, J = 6.5 Hz, 1H), 2.92 (t, J= 8.0 Hz, 4H), 2.87 (s, 3H), 2.45 (s, 3H), 1.73 (d, J = 6.5 Hz, 6H),1.43-1.33 (m, 12H).  15 642.3 ¹H NMR (400 MHz, Methanol-d4) delta 9.08(s, 1H), 0.1 7.90 (s, 1H), 7.80 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H),7.57 (d, J = 1.6 Hz, 1H), 7.42-7.36 (m, 1H), 7.26-7.18 (m, 1H), 5.37 (p,J = 6.8 Hz, 1H), 4.41 (p, J = 8.1 Hz, 1H), 3.81 (q, J = 7.4 Hz, 1H),3.05-2.93 (m, 6H), 2.91 (s, 3H), 2.50 (d, J = 1.8 Hz, 3H), 1.77 (dd, J =6.7, 1.9 Hz, 6H), 1.41 (d, J = 1.9 Hz, 6H), 1.38 (d, J = 1.9 Hz, 6H). 16 634.4 ¹H NMR (400 MHz, Chloroform-d) delta 8.24 (s, 0.1 1H), 8.18(s, 1H), 8.02 (s, 0H), 7.93 (d, J = 2.4 Hz, 0H), 7.66 (d, J = 0.5 Hz,1H), 7.55-7.47 (m, 1H), 7.43 (dd, J = 7.8, 1.4 Hz, 1H), 7.36-7.29 (m,1H), 7.23-7.16 (m, 2H), 6.09 (s, 1H), 4.90 (t, J = 8.9 Hz, 1H), 4.38 (s,1H), 4.01 (s, 1H), 3.67 (d, J = 53.6 Hz, 2H), 3.43 (s, 3H), 2.90 (s,1H), 2.71-2.54 (m, 4H), 2.44 (s, 1H), 1.23 (d, J = 16.2 Hz, 8H), 1.07(s, 3H), 0.97-0.81 (m, 2H).  17 622.4 ¹H NMR (400 MHz, Chloroform-d)delta 8.14 (s, 0.04 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.51 (d, J = 7.1Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.00 (s,1H), 5.17-4.72 (m, 1H), 3.51 (d, J = 10.2 Hz, 2H), 2.80-2.60 (m, 2H),2.05 (d, J = 35.4 Hz, 0H), 1.25 (s, 8H), 0.85 (d, J = 18.2 Hz, 1H), 0.07(d, J = 4.3 Hz, 4H).  18 621.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.34 (s,1H), 0.4 8.85 (d, J = 1.7 Hz, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.19-8.13(m, 1H), 7.98 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.57-7.48 (m, 2H), 7.20(d, J = 8.2 Hz, 1H), 5.35-5.24 (m, 1H), 4.33-4.22 (m, 1H), 3.60-3.49 (m,1H), 3.39 (d, J = 11.8 Hz, 2H), 2.98-2.75 (m, 5H), 2.74 (d, J = 4.6 Hz,3H), 2.31 (s, 3H), 1.84 (d, J = 14.2 Hz, 2H), 1.76-1.59 (m, 3H), 1.56(d, J = 6.5 Hz, 6H), 1.43 (t, J = 14.4 Hz, 1H), 1.31 (s, 6H).  19 697.5¹H NMR (400 MHz, DMSO-d6) delta 9.47 (d, J = 7.7 0.3 Hz, 1H), 8.83 (t, J= 1.8 Hz, 3H), 8.59 (s, 1H), 7.98 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H),7.59 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 8.3, 2.4 Hz, 1H), 7.21 (d, J =8.3 Hz, 1H), 6.11 (t, J = 57.3 Hz, 1H), 5.41-5.29 (m, 1H), 4.32 (h, J =8.5, 7.8 Hz, 1H), 3.58-3.45 (m, 1H), 3.39 (d, J = 11.8 Hz, 2H),2.99-2.74 (m, 5H), 2.31 (s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.76-1.62(m, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.46-1.37 (m, 1H), 1.31 (s, 6H),1.11-1.03 (m, 2H), 0.96-0.88 (m, 2H).  20 670.4 ¹H NMR (400 MHz,DMSO-d6) delta 9.33 (s, 1H), 0.05 8.63 (t, J = 6.1 Hz, 1H), 8.53 (s,1H), 7.87 (s, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (s, 1H), 7.55-7.50 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H),6.23-5.92 (m, 1H), 5.34-5.23 (m, 1H), 4.25 (q, J = 8.3 Hz, 1H),3.69-3.55 (m, 2H), 3.47 (q, J = 7.9 Hz, 1H), 3.37 (d, J = 11.9 Hz, 2H),2.98-2.69 (m, 7H), 2.31 (s, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.54 (d, J =6.5 Hz, 8H), 1.27 (s, 6H).  21 684.4 ¹H NMR (400 MHz, DMSO-d6) delta9.48 (s, 1H), 0.05 8.90 (d, J = 12.5 Hz, 1H), 8.62 (d, J = 6.2 Hz, 1H),8.52 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 7.8,1.4 Hz, 1H), 7.57-7.49 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J =8.4 Hz, 1H), 5.97 (td, J = 56.2, 3.4 Hz, 1H), 5.35 (s, 1H), 4.43- 4.18(m, 2H), 3.54-3.31 (m, 3H), 2.84 (dp, J = 41.0, 11.3, 10.6 Hz, 7H), 2.31(s, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.75-1.46 (m, 9H), 1.41 (t, J = 12.5Hz, 1H), 1.27 (s, 6H), 1.14 (d, J = 7.0 Hz, 3H). 21A 684.4 ¹H NMR (400MHz, DMSO-d6) delta 9.48 (s, 1H), 0.07 (1^(st) 8.90 (d, J = 12.5 Hz,1H), 8.62 (d, J = 6.2 Hz, 1H), eluting peak) 8.52 (d, J = 8.4 Hz, 1H),7.87 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.57-7.49 (m,3H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.97 (td, J =56.2, 3.4 Hz, 1H), 5.35 (s, 1H), 4.43- 4.18 (m, 2H), 3.54-3.31 (m, 3H),2.84 (dp, J = 41.0, 11.3, 10.6 Hz, 7H), 2.31 (s, 3H), 1.82 (d, J = 14.1Hz, 2H), 1.75-1.46 (m, 9H), 1.41 (t, J = 12.5 Hz, 1H), 1.27 (s, 6H),1.14 (d, J = 7.0 Hz, 3H). 21B 684.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.48(s, 1H), 0.07 (2^(nd) 8.90 (d, J = 12.5 Hz, 1H), 8.62 (d, J = 6.2 Hz,1H), eluting peak) 8.52 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H),7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.57-7.49 (m, 3H), 7.38 (d, J = 7.8 Hz,1H), 7.21 (d, J = 8.4 Hz, 1H), 5.97 (td, J = 56.2, 3.4 Hz, 1H), 5.35 (s,1H), 4.43- 4.18 (m, 2H), 3.54-3.31 (m, 3H), 2.84 (dp, J = 41.0, 11.3,10.6 Hz, 7H), 2.31 (s, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.75-1.46 (m,9H), 1.41 (t, J = 12.5 Hz, 1H), 1.27 (s, 6H), 1.14 (d, J = 7.0 Hz, 3H). 22 676.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.36 (s, 1H), 0.07 8.68 (s,1H), 8.47 (s, 1H), 8.23 (t, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.77 (dd, J =7.8, 1.4 Hz, 1H), 7.62- 7.55 (m, 2H), 7.54-7.46 (m, 2H), 7.17 (d, J =8.3 Hz, 1H), 5.30 (q, J = 6.7 Hz, 1H), 4.26 (t, J = 8.2 Hz, 1H), 4.03(q, J = 5.7 Hz, 1H), 3.87-3.77 (m, 1H), 3.42 (dd, J = 39.1, 9.9 Hz, 3H),3.27-3.16 (m, 2H), 2.92 (q, J = 9.8 Hz, 2H), 2.78 (d, J = 11.8 Hz, 4H),2.30 (s, 3H), 1.87-1.47 (m, 15H), 1.39 (d, J = 13.0 Hz, 1H), 1.05 (t, J= 7.2 Hz, 3H).  23 702.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.44 (s, 1H),0.2 8.86 (s, 1H), 8.58-8.52 (m, 1H), 8.50 (d, J = 7.7 Hz, 1H), 7.89 (s,1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.56-7.47(m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 5.34 (p, J = 6.5 Hz, 1H), 4.30 (dq, J= 43.8, 8.2 Hz, 2H), 4.04 (p, J = 5.7 Hz, 2H), 3.83 (dt, J = 10.8, 5.0Hz, 2H), 3.52-3.30 (m, 3H), 3.00-2.84 (m, 2H), 2.78 (td, J = 13.9, 12.7,8.7 Hz, 5H), 2.29 (s, 3H), 2.16 (td, J = 8.3, 4.1 Hz, 2H), 1.93 (dq, J =11.8, 9.4 Hz, 2H), 1.87-1.48 (m, 15H), 1.41 (t, J = 12.3 Hz, 1H).  24648.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.52 (s, 1H), 0.08 8.89 (s, 1H),8.57 (s, 1H), 8.23 (t, J = 5.7 Hz, 1H), 7.87 (s, 1H), 7.75 (dd, J = 7.8,1.4 Hz, 1H), 7.57 (t, J = 1.8 Hz, 2H), 7.49 (dd, J = 8.2, 2.4 Hz, 1H),7.37 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.34 (p, J = 6.6 Hz,1H), 4.23 (p, J = 8.3 Hz, 1H), 3.48 (h, J = 8.4 Hz, 1H), 3.36 (d, J =11.7 Hz, 2H), 3.15 (q, J = 6.6 Hz, 2H), 2.95-2.70 (m, 7H), 2.31 (s, 3H),1.81 (d, J = 14.1 Hz, 2H), 1.56 (d, J = 6.5 Hz, 8H), 1.50-1.34 (m, 3H),1.27 (s, 6H), 0.81 (t, J = 7.4 Hz, 3H).  25 684.4 ¹H NMR (400 MHz,DMSO-d6) delta 9.52 (s, 1H), 0.07 9.00 (s, 1H), 8.62 (s, 1H), 8.39 (t, J= 5.7 Hz, 1H), 7.88 (s, 1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 (d, J= 2.4 Hz, 2H), 7.51 (dd, J = 8.2, 2.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H),7.21 (d, J = 8.3 Hz, 1H), 6.08 (tt, J = 56.5, 4.5 Hz, 1H), 5.36 (p, J =6.5 Hz, 1H), 4.29- 4.16 (m, 1H), 3.48 (h, J = 8.1 Hz, 1H), 3.42-3.29 (m,4H), 2.95-2.70 (m, 6H), 2.32 (s, 3H), 2.04 (ttd, J = 18.0, 7.0, 4.5 Hz,2H), 1.82 (d, J = 14.1 Hz, 2H), 1.57 (d, J = 6.5 Hz, 8H), 1.41 (dd, J =14.7, 10.5 Hz, 1H), 1.27 (s, 6H).  26 646.4 ¹H NMR (400 MHz, DMSO-d6)delta 9.46 (s, 1H), 0.1 8.83 (s, 1H), 8.53 (s, 1H), 8.29 (d, J = 4.5 Hz,1H), 7.88 (s, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.57 (dd, J = 8.1,1.9 Hz, 2H), 7.50 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H),7.20 (d, J = 8.3 Hz, 1H), 5.34 (p, J = 6.6 Hz, 1H), 4.35-4.22 (m, 1H),3.52 (h, J = 8.3 Hz, 1H), 3.39 (d, J = 11.7 Hz, 2H), 2.99-2.75 (m, 7H),2.31 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.57 (d, J = 6.5 Hz, 9H), 1.43(t, J = 12.5 Hz, 1H), 1.30 (s, 6H), 0.65 (td, J = 7.0, 4.7 Hz, 2H),0.51-0.42 (m, 2H).  27 696.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.51 (s,1H), 0.07 8.90 (d, J = 2.9 Hz, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 7.89 (s,1H), 7.75 (dd, J = 7.7, 1.4 Hz, 1H), 7.62- 7.49 (m, 3H), 7.39 (d, J =7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.09 (t, J = 57.3 Hz, 1H), 5.36(p, J = 6.6 Hz, 1H), 4.35-4.22 (m, 1H), 3.58-3.32 (m, 4H), 3.02-2.74 (m,6H), 2.31 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.77-1.52 (m, 7H),1.49-1.35 (m, 1H), 1.30 (s, 7H), 1.11-1.04 (m, 2H), 0.88 (hept, J = 2.5Hz, 2H).  28 684.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.40 (d, J = 0.1 10.0Hz, 1H), 8.76 (s, 1H), 8.67 (t, J = 6.4 Hz, 1H), 8.55 (s, 1H), 7.89 (s,1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.61-7.48 (m, 3H), 7.38 (d, J = 7.8Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.32 (p, J = 6.5 Hz, 1H), 4.25 (p, J= 8.3 Hz, 1H), 3.67 (td, J = 13.9, 6.3 Hz, 2H), 3.56-3.32 (m, 3H),3.00-2.72 (m, 6H), 2.33 (s, 3H), 1.84 (d, J = 14.2 Hz, 2H), 1.76-1.49(m, 12H), 1.41 (q, J = 12.7, 11.4 Hz, 1H), 1.29 (s, 6H).  29 666.4 ¹HNMR (400 MHz, DMSO-d6) delta 9.47 (s, 1H), 0.1 8.85 (d, J = 15.6 Hz,1H), 8.58 (d, J = 6.8 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H),7.76 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 20.7, 9.2 Hz, 3H), 7.39 (d, J =7.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 5.44-5.28 (m, 1H), 4.41 (d, J =5.7 Hz, 1H), 4.27 (dt, J = 12.9, 5.8 Hz, 3H), 3.58-3.31 (m, 3H),2.99-2.71 (m, 7H), 2.32 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.77-1.53(m, 8H), 1.48-1.34 (m, 1H), 1.29 (s, 6H), 1.11 (d, J = 6.6 Hz, 3H).  30666.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.55 (s, 1H), 0.1 9.01-8.92 (m,1H), 8.66-8.61 (m, 1H), 8.32 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.76 (d,J = 7.7 Hz, 1H), 7.55 (ddd, J = 17.7, 7.1, 1.8 Hz, 3H), 7.40 (d, J = 7.7Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.38 (p, J = 6.3, 5.9 Hz, 1H), 4.41(dd, J = 5.6, 1.9 Hz, 1H), 4.35-4.22 (m, 3H), 3.58-3.32 (m, 3H),3.01-2.71 (m, 6H), 2.33 (s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.59 (d, J =6.6 Hz, 8H), 1.42 (ddt, J = 16.1, 12.5, 6.3 Hz, 1H), 1.29 (s, 6H), 1.11(d, J = 6.7 Hz, 3H).  31 684.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.49 (s,1H), 0.08 8.87 (d, J = 13.8 Hz, 1H), 8.61 (d, J = 7.0 Hz, 2H), 7.89 (d,J = 1.0 Hz, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 (t, J = 9.4 Hz,3H), 7.39 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 5.35 (s, 1H),4.60 (d, J = 4.5 Hz, 2H), 4.48 (d, J = 4.1 Hz, 2H), 4.26 (p, J = 8.3 Hz,1H), 3.49 (q, J = 8.1 Hz, 1H), 3.39 (d, J = 11.8 Hz, 2H), 2.98-2.73 (m,6H), 2.33 (s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.77-1.49 (m, 8H),1.49-1.36 (m, 1H), 1.29 (s, 6H).  32 738.4 ¹H NMR (400 MHz, DMSO-d6)delta 9.48 (s, 1H), 0.08 8.84 (d, J = 12.2 Hz, 2H), 8.58 (s, 1H), 7.90(s, 1H), 7.76 (dd, J = 7.9, 1.4 Hz, 1H), 7.64-7.48 (m, 4H), 7.21 (d, J =8.2 Hz, 1H), 6.09 (t, J = 57.3 Hz, 1H), 5.35 (p, J = 6.7 Hz, 1H),4.35-4.21 (m, 1H), 4.12- 4.02 (m, 2H), 3.85 (dt, J = 10.9, 5.0 Hz, 2H),3.56- 3.34 (m, 3H), 2.96 (qd, J = 9.2, 2.6 Hz, 2H), 2.87- 2.73 (m, 4H),2.31 (s, 3H), 1.89-1.52 (m, 15H), 1.41 (d, J = 12.2 Hz, 1H), 1.10-1.04(m, 2H), 0.89 (hept, J = 3.5, 2.7 Hz, 2H).  33 605.3 ¹H NMR (400 MHz,Methanol-d4) delta 8.77 (d, J = 0.2 0.6 Hz, 1H), 7.89 (s, 1H), 7.67 (dd,J = 7.8, 1.5 Hz, 1H), 7.58 (dt, J = 2.5, 0.4 Hz, 1H), 7.46 (d, J = 1.4Hz, 1H), 7.41 (dt, J = 8.4, 0.6 Hz, 1H), 7.37-7.30 (m, 2H), 4.31-4.20(m, 1H), 4.00-3.91 (m, 1H), 3.72-3.63 (m, 1H), 3.53 (d, J = 12.2 Hz,2H), 3.02 (qd, J = 9.0, 2.7 Hz, 2H), 2.88 (tdd, J = 12.4, 6.5, 3.3 Hz,3H), 2.56-2.52 (m, 3H), 2.01 (d, J = 14.5 Hz, 2H), 1.88 (d, J = 13.3 Hz,1H), 1.83-1.66 (m, 1H), 1.56 (qt, J = 12.8, 3.8 Hz, 1H), 1.38-1.23 (m,11H).  34 619.4 ¹H NMR (400 MHz, Methanol-d4) delta 8.75-8.72 0.6 (m,1H), 7.90 (d, J = 0.5 Hz, 1H), 7.67 (dd, J = 7.8, 1.5 Hz, 1H), 7.46 (d,J = 1.4 Hz, 1H), 7.44-7.39 (m, 2H), 7.36-7.31 (m, 2H), 4.32-4.20 (m,1H), 3.92 (dq, J = 10.8, 3.6 Hz, 1H), 3.68 (p, J = 8.0 Hz, 1H), 3.54 (d,J = 12.4 Hz, 2H), 3.03 (qd, J = 9.0, 2.7 Hz, 2H), 2.94-2.84 (m, 7H),2.49 (s, 3H), 2.01 (d, J = 14.6 Hz, 2H), 1.88 (d, J = 13.5 Hz, 1H), 1.75(q, J = 13.8, 13.3 Hz, 2H), 1.56 (qt, J = 13.4, 4.1Hz, 1H), 1.37-1.23(m, 11H).  35 680.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.51 (s, 1H), 0.18.90 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.21 (q, J = 4.6 Hz, 1H), 7.87(s, 1H), 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.59 (dd, J = 14.3, 8.0 Hz,2H), 7.46 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 12.0 Hz, 1H), 5.33 (p, J =6.6 Hz, 1H), 4.16 (p, J = 8.3 Hz, 1H), 4.05 (dt, J = 11.5, 5.7 Hz, 2H),3.84 (dt, J = 10.9, 5.1 Hz, 2H), 3.52 (h, J = 8.4 Hz, 1H), 3.39 (d, J =11.7 Hz, 2H), 2.93 (qd, J = 9.3, 2.7 Hz, 2H), 2.87-2.70 (m, 6H), 2.39(s, 3H), 1.90-1.54 (m, 15H), 1.43 (ddt, J = 12.2, 7.4, 3.9 Hz, 1H).  36620.4 ¹H NMR (400 MHz, Methanol-d4) delta 8.84 (s, 1H), 0.1 8.41 (d, J =2.9 Hz, 1H), 7.83-7.76 (m, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.68 (d, J =1.1 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.32(d, J = 8.3 Hz, 1H), 4.47 (q, J = 8.0 Hz, 1H), 4.19 (d, J = 27.5 Hz,2H), 3.83 (s, 0H), 3.71 (t, J = 8.0 Hz, 1H), 3.51 (d, J = 11.7 Hz, 1H),3.42 (d, J = 12.6 Hz, 1H), 3.02 (ddt, J = 52.7, 41.1, 10.9 Hz, 6H), 2.49(s, 3H), 2.01- 1.67 (m, 3H), 1.53-1.36 (m, 10H).  37 620.4 ¹H NMR (400MHz, Methanol-d4) delta 8.60 (d, J = 0.1 4.3 Hz, 1H), 8.46 (d, J = 2.4Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.67 (s,1H), 7.53 (dd, J = 8.3, 2.5 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.31 (d,J = 8.3 Hz, 1H), 4.47 (t, J = 8.1 Hz, 1H), 4.22 (s, 1H), 4.10 (s, 1H),3.72 (t, J = 7.8 Hz, 1H), 3.59- 3.38 (m, 1H), 3.14 (d, J = 8.5 Hz, 1H),3.06 (d, J = 13.1 Hz, 4H), 2.91 (d, J = 11.4 Hz, 0H), 2.49 (s, 3H),2.01-1.65 (m, 3H), 1.42 (s, 12H).  38 646 ¹H NMR (400 MHz, Methanol-d4)delta 8.31 (s, 1H), 0.07 8.19 (s, 1H), 7.84-7.55 (m, 4H), 7.37 (d, J =7.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.47-4.36 (m, 1H), 4.04-3.95 (m,1H), 3.65-335 (m, 3H), 3.20-2.50 (m, 13H), 2.39 (s, 3H), 1.92-176 (s,2H), 1.53-1.30 (m, 10H), 1.07 (s, 6H).  39 622.3 ¹H NMR (400 MHz,DMSO-d6) delta 10.12-9.97 0.1 (m), 8.70, 8.46, 8.15 (d, J = 4.6 Hz),7.88, 7.78 (dd, J = 7.8, 1.4 Hz), 7.63-7.47 (m), 7.39 (d, J = 7.7 Hz),7.20 (d, J = 8.3 Hz), 5.30 (p, J = 6.5 Hz), 4.42-4.21 (m), 4.02 (d, J =13.3 Hz), 3.75-3.53 (m), 3.40 (d, J = 12.2 Hz), 3.17-2.62 (m), 2.32,1.56 (d, J = 6.5 Hz), 1.30 (s, 6H).  40 638.5 ¹H NMR (400 MHz, DMSO-d6)delta 9.35 (d, J = 9.4 0.1 Hz, 1H), 8.54-8.30 (m, 3H), 8.02 (d, J = 2.7Hz, 1H), 7.95-7.72 (m, 3H), 7.59 (d, J = 1.5 Hz, 1H), 7.43 (dd, J =21.6, 8.3 Hz, 2H), 4.40-4.23 (m, 1H), 4.12 (p, J = 6.4 Hz, 1H),3.56-3.26 (m, 3H), 3.07- 2.58 (m, 8H), 1.99-1.50 (m, 6H), 1.45-1.15 (m,11H).  41 773.7 ¹H NMR (400 MHz, DMSO-d6) delta 9.37 (s, 1H), 0.07 8.44(s, 1H), 8.39 (q, J = 3.6, 3.0 Hz, 2H), 7.97 (d, J = 2.6 Hz, 1H), 7.91(dd, J = 8.8, 2.7 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J = 7.9, 1.5 Hz, 1H),7.64 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.8 Hz,1H), 4.40-4.28 (m, 1H), 4.13 (s, 1H), 4.04-3.81 (m, 2H), 3.41 (d, J =11.8 Hz, 3H), 3.06-2.79 (m, 5H), 2.77 (d, J = 4.6 Hz, 3H), 2.13 (d, J =6.9 Hz, 6H), 1.90-1.53 (m, 12H), 1.41 (d, J = 13.1 Hz, 1H), 1.24 (d, J =7.5 Hz, 5H).  42 755.5 ¹H NMR (400 MHz, Chloroform-d) delta 7.95 (s,0.06 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.83 (d, J = 12.6 Hz, 2H), 7.77 (d,J = 7.8 Hz, 1H), 7.68 (d, J = 1.4 Hz, 1H), 7.56 (s, 1H), 7.22 (d, J =8.3 Hz, 2H), 5.87 (d, J = 5.0 Hz, 1H), 5.00 (dt, J = 17.5, 6.4 Hz, 2H),4.85 (dt, J = 9.5, 4.9 Hz, 2H), 4.39 (t, J = 8.7 Hz, 1H), 4.26 (d, J =14.0 Hz, 1H), 4.18-4.01 (m, 1H), 3.86 (dd, J = 13.5, 8.9 Hz, 2H), 3.74(s, 1H), 3.28 (d, J = 28.3 Hz, 2H), 3.00 (dd, J = 5.0, 1.5 Hz, 3H), 2.67(dd, J = 17.8, 9.7 Hz, 5H), 2.45 (d, J = 1.3 Hz, 3H), 2.41- 2.29 (m,2H), 1.84 (d, J = 11.3 Hz, 3H), 1.65 (d, J = 9.9 Hz, 2H), 1.42 (d, J =7.6 Hz, 5H), 1.31-1.23 (m, 4H).  43 765.6 ¹H NMR (400 MHz, DMSO-d6)delta 9.82 (s, 0H), 0.08 9.35 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.18(d, J = 4.6 Hz, 1H), 7.89 (s, 0H), 7.85 (d, J = 2.4 Hz, 1H), 7.83-7.77(m, 2H), 7.76 (s, 1H), 7.64-7.55 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 4.25(t, J = 8.5 Hz, 1H), 4.19- 4.06 (m, 1H), 4.02-3.70 (m, 6H), 3.68-3.55(m, 1H), 3.23 (s, 1H), 2.98-2.78 (m, 5H), 2.74 (dd, J = 4.7, 0.6 Hz,3H), 2.69-2.64 (m, 0H), 2.36-2.25 (m, 3H), 2.11 (d, J = 10.9 Hz, 7H),1.93 (d, J = 11.4 Hz, 1H), 1.82-1.56 (m, 8H), 1.36 (s, 1H), 1.25 (d, J =8.0 Hz, 4H).  44 713.5 ¹H NMR (400 MHz, DMSO-d6) delta 8.30 (d, J = 0.40.2 Hz, 1H), 8.23-8.15 (m, 2H), 8.12 (d, J = 1.5 Hz, 1H), 7.94 (dd, J =8.3, 2.4 Hz, 1H), 7.87-7.81 (m, 2H), 7.77 (s, 1H), 7.51 (d, J = 7.9 Hz,1H), 7.21 (d, J = 8.5 Hz, 1H), 4.60-4.47 (m, 1H), 4.17-4.09 (m, 1H),3.97-3.81 (m, 2H), 3.73 (q, J = 6.3 Hz, 2H), 3.06-2.93 (m, 1H), 2.77 (d,J = 4.6 Hz, 3H), 2.72- 2.57 (m, 4H), 2.31 (s, 4H), 2.24 (d, J = 8.8 Hz,1H), 2.09 (d, J = 0.8 Hz, 3H), 1.88-1.72 (m, 2H), 1.73- 1.55 (m, 5H),1.55-1.29 (m, 3H), 1.30-1.23 (m, 4H), 1.22-1.17 (m, 2H).  45 648.5 ¹HNMR (400 MHz, DMSO-d6) delta 9.39 (d, J = 9.6 0.1 Hz, 1H), 8.68 (s, 1H),8.47 (s, 1H), 8.14 (q, J = 4.5 Hz, 1H), 7.99-7.75 (m, 2H), 7.67-7.42 (m,3H), 7.23 (dd, J = 37.4, 8.1 Hz, 2H), 5.28 (p, J = 6.5 Hz, 1H), 4.24 (t,J = 8.2 Hz, 1H), 3.56-3.25 (m, 3H), 3.04-2.62 (m, 9H), 2.30 (s, 3H),1.95-1.20 (m, 16H), 0.50 (t, J = 7.3 Hz, 6H).  46 703.5 ¹H NMR (400 MHz,DMSO-d6) delta 9.38 (d, J = 9.8 0.1 Hz, 1H), 8.71 (s, 1H), 8.47 (s, 1H),8.14 (q, J = 4.6 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.9, 1.5 Hz, 1H),7.62-7.43 (m, 4H), 7.17 (d, J = 9.0 Hz, 1H), 5.28 (p, J = 6.5 Hz, 1H),4.63-3.23 (m, 7H), 3.08-2.62 (m, 10H), 2.30 (s, 3H), 2.07 (s, 3H),1.91-1.28 (m, 16H).  47 721.6 ¹H NMR (400 MHz, DMSO-d6) delta 9.44 (s,1H), 0.2 8.56-8.24 (m, 3H), 8.05-7.71 (m, 4H), 7.66-7.33 (m, 3H),4.70-3.24 (m, 12H), 3.10-2.59 (m, 6H), 2.07 (s, 3H), 1.94-1.12 (m, 14H). 48 717.6 ¹H NMR (400 MHz, DMSO-d6) delta 9.35 (s, 1H), 0.1 8.67 (s,1H), 8.43 (s, 1H), 8.14 (d, J = 4.7 Hz, 1H), 7.89 (s, 1H), 7.75 (dd, J =8.2, 1.4 Hz, 1H), 7.65- 7.33 (m, 4H), 7.16 (d, J = 8.1 Hz, 1H), 5.08 (q,J = 6.6 Hz, 1H), 4.55-3.27 (m, 7H), 3.12-2.63 (m, 10H), 2.29 (s, 3H),2.07 (s, 3H), 1.96-1.50 (m, 14H), 1.41 (t, J = 12.9 Hz, 1H), 0.76 (t, J= 7.3 Hz, 3H).  49 689.5 ¹H NMR (400 MHz, DMSO-d6) delta 9.34 (s, 1H),0.1 8.44 (d, J = 29.5 Hz, 2H), 8.14 (q, J = 4.5 Hz, 1H), 7.92-7.73 (m,2H), 7.69-7.42 (m, 4H), 7.18 (d, J = 8.3 Hz, 1H), 4.62 (q, J = 7.1 Hz,2H), 4.26 (p, J = 8.2 Hz, 1H), 4.12-3.25 (m, 8H), 3.07-2.63 (m, 8H),2.30 (s, 3H), 2.07 (s, 3H), 1.93-1.50 (m, 10H), 1.38 (t, J = 7.2 Hz,3H).  50 717.6 ¹H NMR (400 MHz, DMSO-d6) delta 9.44 (d, J = 0.1 10.1 Hz,1H), 8.51 (s, 1H), 8.29-8.11 (m, 2H), 7.95- 7.73 (m, 4H), 7.67-7.45 (m,2H), 7.21 (d, J = 8.4 Hz, 1H), 5.05-4.00 (m, 6H), 3.91-3.27 (m, 11H),3.04-2.66 (m, 7H), 2.30 (s, 3H), 2.03-1.09 (m, 11H).  51 727.6 ¹H NMR(400 MHz, DMSO-d6) delta 9.38 (d, J = 9.8 0.1 Hz, 1H), 8.44 (s, 1H),8.32-8.04 (m, 2H), 7.98-7.73 (m, 4H), 7.74-7.51 (m, 2H), 7.21 (d, J =8.4 Hz, 1H), 4.47-3.25 (m, 8H), 3.07-2.65 (m, 9H), 2.30 (s, 3H),2.12-1.14 (m, 16H), 0.87-0.58 (m, 4H).  52 729.6 ¹H NMR (400 MHz,DMSO-d6) delta 9.32 (s, 1H), 0.09 8.33 (s, 1H), 8.22-8.13 (m, 2H),7.95-7.76 (m, 4H), 7.71-7.48 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 4.32 (t,J = 8.1 Hz, 1H), 4.12 (d, J = 4.4 Hz, 1H), 3.84 (d, J = 33.9 Hz, 3H),3.41 (s, 3H), 3.00-2.65 (m, 9H), 2.29 (s, 3H), 1.91-1.53 (m, 9H),1.43-1.14 (m, 5H), 1.04 (dd, J = 11.3, 6.6 Hz, 7H).  53 763.5 ¹H NMR(400 MHz, DMSO-d6) delta 9.38 (d, J = 9.6 0.08 Hz, 1H), 8.67 (s, 1H),8.49-8.34 (m, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.66-7.42 (m,4H), 7.17 (d, J = 12.1 Hz, 1H), 5.38-5.14 (m, 1H), 4.33-3.93 (m, 2H),3.89-3.60 (m, 2H), 3.57-3.21 (m, 3H), 3.03-2.65 (m, 7H), 2.41-2.18 (m,5H), 1.90-1.47 (m, 16H), 1.38 (d, J = 13.2 Hz, 1H), 1.14-0.90 (m, 9H). 54 735.5 ¹H NMR (400 MHz, DMSO-d6) delta 9.42 (d, J = 9.6 0.4 Hz, 1H),8.58 (s, 1H), 8.39 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.84 (s, 1H),7.76-7.62 (m, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7.18 (d, J = 12.1 Hz, 1H),4.63 (q, J = 7.1 Hz, 2H), 4.29-3.28 (m, 9H), 3.07-2.62 (m, 5H), 2.35 (s,3H), 2.06 (s, 3H), 1.95-1.23 (m, 14H), 1.07 (d, J = 6.5 Hz, 6H).  55793.5 ¹H NMR (400 MHz, DMSO-d6) delta 9.35 (s, 1H), 0.2 8.66 (s, 1H),8.40 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.73-7.42 (m, 4H),7.17 (d, J = 12.1 Hz, 1H), 5.27 (q, J = 6.7 Hz, 1H), 4.45-3.68 (m, 8H),3.55-3.22 (m, 3H), 3.05-2.59 (m, 7H), 2.34 (s, 3H), 1.91-1.44 (m, 15H),1.35 (s, 5H), 1.07 (d, J = 6.6 Hz, 6H).  56 735.5 ¹H NMR (400 MHz,DMSO-d6) delta 9.40 (d, J = 9.8 0.3 Hz, 1H), 8.53 (s, 1H), 8.36 (s, 1H),8.26 (t, J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.75-7.60 (m, 2H), 7.54-7.41 (m,2H), 7.18 (d, J = 12.0 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.18 (p, J =8.3 Hz, 1H), 3.96-3.61 (m, 4H), 3.55-3.08 (m, 5H), 3.04-2.65 (m, 6H),2.43- 2.31 (m, 5H), 1.89-1.23 (m, 13H), 1.03 (dt, J = 9.5, 7.3 Hz, 6H). 57 606.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.67 (d, J = 9.5 0.2 Hz, 1H),9.01 (s, 1H), 8.62-8.40 (m, 1H), 8.15 (q, J = 4.5 Hz, 1H), 7.71 (s, 1H),7.59-7.47 (m, 2H), 7.31 (dd, J = 7.7, 1.5 Hz, 1H), 7.18 (dt, J = 8.0,0.7 Hz, 1H), 7.09-6.94 (m, 2H), 5.59-5.15 (m, 1H), 3.88 (p, J = 8.2 Hz,1H), 3.51-3.29 (m, 3H), 3.12 (s, 2H), 2.84-2.68 (m, 5H), 2.57-2.44 (m,3H), 2.40-2.25 (m, 5H), 1.83 (d, J = 14.2 Hz, 2H), 1.56 (d, J = 6.5 Hz,8H), 1.46-1.34 (m, 1H), 1.24 (s, 6H).  58a 701.61 ¹H NMR (400 MHz,DMSO-d6) delta 9.40 (s, 1H), 0.1 8.51 (s, 1H), 8.25 (s, 1H), 8.17 (q, J= 4.6 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.85-7.77 (m, 2H), 7.64 (d, J =1.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.32(p, J = 8.3 Hz, 1H), 4.20-4.12 (m, 1H), 3.89 (dd, J = 31.5, 7.9 Hz, 2H),3.73 (dd, J = 11.9, 5.5 Hz, 2H), 3.52 (q, J = 7.9 Hz, 1H), 3.40 (d, J =11.8 Hz, 2H), 3.07-2.72 (m, 8H), 2.32 (s, 3H), 2.12-2.06 (m, 4H),1.89-1.54 (m, 8H), 1.32-1.23 (m, 3H).  58 604.3 ¹H NMR (400 MHz,DMSO-d6) delta 9.68 (d, J = 9.6 0.6 Hz, 1H), 8.62 (s, 1H), 8.31-7.98 (m,2H), 7.94 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.3, 2.4 Hz, 1H), 7.61 (s,1H), 7.37 (dd, J = 7.7, 1.5 Hz, 1H), 7.29-6.97 (m, 3H), 4.17 (p, J = 5.3Hz, 1H), 3.93 (p, J = 8.2 Hz, 1H), 3.58-3.27 (m, 3H), 3.13 (s, 2H), 2.75(d, J = 4.6 Hz, 5H), 2.61-2.51 (m, 2H), 2.41-2.21 (m, 4H), 1.93-1.00 (m,17H).  59 763.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.36 (d, J = 9.6 0.3 Hz,1H), 8.70 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.72-7.62(m, 1H), 7.57-7.44 (m, 3H), 7.17 (d, J = 12.1 Hz, 1H), 5.36-5.20 (m,1H), 4.20 (p, J = 8.5 Hz, 1H), 3.91-3.80 (m, 2H), 3.79-3.63 (m, 2H),3.52 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.02-2.84 (m, 2H),2.85-2.72 (m, 4H), 2.35 (s, 3H), 2.08 (s, 3H), 1.90-1.62 (m, 8H),1.62-1.54 (m, 7H), 1.47-1.35 (m, 1H), 1.33 (s, 9H).  60 749.4 ¹H NMR(400 MHz, DMSO-d6) delta 9.31 (s, 1H), 0.2 8.62 (s, 1H), 8.38 (s, 1H),8.27 (t, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.61(d, J = 8.2 Hz, 1H), 7.53-7.49 (m, 2H), 7.19 (d, J = 12.0 Hz, 1H),5.33-5.21 (m, 1H), 4.19 (p, J = 8.1 Hz, 1H), 3.93-3.65 (m, 4H), 3.51 (q,J = 8.0 Hz, 1H), 3.39 (d, J = 12.0 Hz, 2H), 3.22 (p, J = 7.1 Hz, 2H),3.04-2.71 (m, 5H), 2.44-2.34 (m, 6H), 1.84 (d, J = 14.1 Hz, 2H),1.80-1.53 (m, 13H), 1.48-1.34 (m, 1H), 1.08- 1.01 (m, 6H).  61 743.4 ¹HNMR (400 MHz, DMSO-d6) delta 9.50 (s, 1H), 0.2 8.65 (s, 1H), 8.38 (s,1H), 8.20 (q, J = 4.4 Hz, 1H), 7.91 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H),7.61 (s, 1H), 7.51 (s, 1H), 7.19 (d, J = 12.1 Hz, 1H), 6.73-6.40 (m,1H), 5.28 (p, J = 6.3 Hz, 1H), 4.20 (p, J = 8.4 Hz, 1H), 3.95-3.25 (m,8H), 2.97-2.87 (m, 2H), 2.87- 2.71 (m, 8H), 2.38 (s, 3H), 2.02 (s, 3H),1.84 (d, J = 14.2 Hz, 2H), 1.76-1.55 (m, 10H), 1.48-1.36 (m, 1H).  62753.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.66-9.53 (m, 0.1 1H), 8.71 (s,1H), 8.51 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J =7.8, 1.5 Hz, 1H), 7.64 (s, 1H), 7.58-7.44 (m, 2H), 7.18 (d, J = 8.4 Hz,1H), 6.59 (t, J = 53.7 Hz, 2H), 5.32 (p, J = 6.5 Hz, 1H), 4.28 (p, J =8.4 Hz, 1H), 4.11-3.98 (m, 1H), 3.80 (s, 2H), 3.64 (s, 2H), 3.54-3.30(m, 5H), 2.98-2.88 (m, 2H), 2.88-2.73 (m, 4H), 2.31 (s, 3H), 2.26-1.89(m, 4H), 1.84 (d, J = 14.1 Hz, 2H), 1.76-1.59 (m, 3H), 1.57 (d, J = 6.5Hz, 6H), 1.48-1.35 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H).  63 642.4 ¹H NMR(400 MHz, DMSO-d6) delta 9.34 (s, 1H), 0.1 8.68-8.54 (m, 1H), 8.40-8.30(m, 1H), 8.00-7.88 (m, 1H), 7.81-7.74 (m, 1H), 7.62-7.50 (m, 3H),7.48-7.31 (m, 2H), 6.16-5.69 (m, 1H), 5.27-5.22 (m, 1H), 4.23 (s, 2H),2.99-2.63 (m, 6H), 2.47-2.30 (m, 4H), 1.98-1.14 (m, 16H).  64 745.4 ¹HNMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.39 0.1 (s, 1H), 8.98 (s, 1H),8.74-8.61 (m, 3H), 8.00 (s, 1H), 7.76-7.66 (m, 1H), 7.50-7.30 (m, 1H),6.06 (t, J = 56.9 Hz, 1H), 5.34-5.22 (m, 1H), 4.30-4.10 (m, 1H), 3.97(s, 1H), 3.66-3.55 (m, 1H), 3.40-3.35 (m, 1H), 3.30-3.21 (m, 1H), 2.95(d, J = 8.1 Hz, 1H), 2.90-2.81 (m, 1H), 2.65 (d, J = 19.5 Hz, 1H), 2.29(d, J = 2.2 Hz, 3H), 2.01-1.88 (m, 1H), 1.74 (t, J = 12.2 Hz, 4H),1.67-1.55 (m, 7H), 1.53 (d, J = 6.5 Hz, 1H), 1.39 (t, J = 8.1 Hz, 1H),1.30 (s, 6H), 1.16- 1.04 (m, 2H), 0.95-0.90 (m, 2H).  65 714.4 ¹H NMR(400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.84 0.1 (s, 1H), 8.75 (s, 1H), 8.45(s, 1H), 7.85 (s, 1H), 7.68- 7.60 (m, 2H), 7.46 (d, J = 1.5 Hz, 1H),7.36 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 12.1 Hz, 1H), 6.07 (t, J = 57.2Hz, 1H), 5.30 (p, J = 6.6 Hz, 1H), 4.20 (p, J = 8.4 Hz, 1H), 3.51 (p, J= 8.2 Hz, 1H), 3.40 (d, J = 11.9 Hz, 2H), 3.00-2.70 (m, 7H), 2.36 (s,3H), 1.91- 1.33 (m, 11H), 1.28 (s, 6H), 1.10-1.03 (m, 2H), 0.88 (s, 2H). 66 726.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.85 0.09 (d, J =2.9 Hz, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.42 (s, 1H), 7.83 (s, 1H),7.68-7.54 (m, 2H), 7.47-7.31 (m, 2H), 7.22 (d, J = 11.9 Hz, 1H), 6.07(t, J = 57.1 Hz, 1H), 5.29 (p, J = 6.5 Hz, 1H), 4.22-4.04 (m, 1H), 3.96(s, 1H), 3.78-3.55 (m, 1H), 3.44-3.19 (m, 1H), 3.02-2.60 (m, 6H), 2.36(s, 3H), 1.98 (t, J = 13.8 Hz, 1H), 1.84-1.50 (m, 11H), 1.28 (s, 6H),1.07 (q, J = 5.0, 4.6 Hz, 2H), 0.89 (s, 3H).  67 715.4 ¹H NMR (400 MHz,DMSO-d6) δ 9.37 (d, J = 9.6 0.3 Hz, 1H), 8.86 (s, 1H), 8.74-8.65 (m,2H), 8.45 (s, 1H), 7.96 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.63 (d, J =8.1 Hz, 1H), 7.22 (d, J = 12.0 Hz, 1H), 6.09 (t, J = 57.2 Hz, 1H),5.35-5.24 (m, 1H), 4.32-4.19 (m, 1H), 3.58-3.45 (m, 1H), 3.40 (d, J =11.9 Hz, 2H), 2.97-2.75 (m, 6H), 2.36 (s, 3H), 1.85 (d, J = 14.2 Hz,2H), 1.76-1.61 (m, 3H), 1.59 (d, J = 6.5 Hz, 6H), 1.42 (t, J = 12.6 Hz,1H), 1.29 (s, 6H), 1.06 (t, J = 3.6 Hz, 2H), 0.92 (d, J = 6.0 Hz, 2H). 68 735.4 ¹H NMR (400 MHz, DMSO-d6) delta 11.20-10.66 0.2 (m, 1H),9.82-9.48 (m, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 8.20 (d, J = 4.7 Hz, 1H),8.02-7.12 (m, 6H), 5.29 (p, J = 6.5 Hz, 1H), 4.97-4.42 (m, 5H), 4.25-4.08 (m, 1H), 3.64-3.13 (m, 7H), 3.00-2.86 (m, 2H), 2.86-2.71 (m, 7H),2.45-1.77 (m, 9H), 1.78- 1.51 (m, 9H), 1.51-1.34 (m, 1H).  69 749.4 ¹HNMR (400 MHz, DMSO-d6) delta 10.90-10.64 0.1 (m, 1H), 9.60-9.40 (m, 1H),8.60 (s, 1H), 8.42-8.35 (m, 1H), 8.28 (t, J = 5.6 Hz, 1H), 7.99-7.11 (m,5H), 5.27 (p, J = 6.4 Hz, 1H), 4.95-4.65 (m, 5H), 4.55- 4.13 (m, 3H),3.61-3.33 (m, 4H), 3.22 (p, J = 7.0 Hz, 3H), 2.98-2.87 (m, 2H),2.86-2.74 (m, 4H), 2.40-1.96 (m, 7H), 1.88-1.76 (m, 3H), 1.76-1.53 (m,9H), 1.48-1.35 (m, 1H), 1.07 (t, J = 7.2 Hz, 3H).  70 769.4 ¹H NMR (400MHz, DMSO-d6) delta 8.68 (s, 1H), 0.7 8.39 (s, 1H), 8.21 (d, J = 4.6 Hz,1H), 8.01-7.36 (m, 5H), 7.20 (d, J = 11.9 Hz, 2H), 5.29 (p, J = 6.4 Hz,1H), 4.96-4.69 (m, 5H), 4.18 (p, J = 8.6, 8.1 Hz, 1H), 3.94-3.03 (m,9H), 3.03-2.82 (m, 3H), 2.80- 2.65 (m, 4H), 2.60-2.44 (m, 1H, overlappedwith solvent), 2.38 (s, 3H), 2.43-1.69 (m, 5H), 1.59 (d, J = 6.6 Hz,6H).  71 739.4 ¹H NMR (400 MHz, DMSO-d6) delta 11.18-10.61 0.1 (m, 2H),8.66 (s, 1H), 8.38 (s, 1H), 8.21 (d, J = 4.6 Hz, 1H), 8.02-7.10 (m, 6H),5.64-5.39 (m, 1H), 5.28 (p, J = 6.7 Hz, 1H), 4.95-4.44 (m, 5H), 4.23 (s,1H), 3.99-3.14 (m, 9H), 3.03-2.85 (m, 2H), 2.83- 2.71 (m, 5H), 2.45-1.72(m, 9H), 1.59 (d, J = 6.5 Hz, 6H).  72 739.4 ¹H NMR (400 MHz, DMSO-d6)delta 11.21-10.64 0.2 (m, 2H), 8.65 (s, 1H), 8.37 (s, 1H), 8.21 (d, J =4.6 Hz, 1H), 8.01-7.07 (m, 6H), 5.51 (d, J = 53.0, 1H), 5.29 (p, J = 6.4Hz, 1H), 4.86-4.46 (m, 5H), 4.31- 4.16 (m, 1H), 3.97-3.15 (m, 9H), 2.95(p, J = 9.6 Hz, 1H), 2.86-2.69 (m, 4H), 2.43-1.72 (m, 9H), 1.59 (d, J =6.5 Hz, 6H).  73 745.5 ¹H NMR (400 MHz, DMSO-d6) delta 11.23-10.72 0.1(m, 1H), 9.83-9.53 (m, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 8.12 (d, J = 7.9Hz), 8.03-7.21 (m, 6H), 7.18 (d, J = 8.4 Hz, 1H), 5.32 (p, J = 6.6 Hz,1H), 4.95- 4.40 (m, 5H), 4.28 (p, J = 8.4 Hz, 1H), 4.05 (hex, J = 6.8Hz, 1H), 3.70-3.13 (m, 7H), 2.93 (q, J = 9.3 Hz, 2H), 2.87-2.74 (m, 4H),2.40-1.50 (m, 19H), 1.50- 1.32 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H).  74735.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.37 (s, 1H), 0.2 8.76-8.70 (m,1H), 8.43 (s, 1H), 8.27 (t, J = 5.6 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J =8.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.56-7.46 (m, 2H), 7.20 (d, J =12.0 Hz, 1H), 5.36-5.20 (m, 1H), 4.17 (p, J = 8.3 Hz, 1H), 3.93-3.79 (m,2H), 3.77-3.66 (m, 2H), 3.51 (q, J = 8.1 Hz, 1H), 3.39 (d, J = 11.7 Hz,2H), 3.22 (p, J = 7.1 Hz, 2H), 3.03-2.71 (m, 6H), 2.38 (s, 3H), 2.08 (s,3H), 1.89-1.62 (m, 8H), 1.62-1.54 (m, 7H), 1.48-1.34 (m, 1H), 1.06 (t, J= 7.2, 3H).  75 763.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.34 (s, 1H), 0.28.69 (s, 1H), 8.40 (s, 1H), 8.27 (t, J = 5.9 Hz, 1H), 7.86 (s, 1H), 7.65(d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.18(d, J = 12.1 Hz, 1H), 5.34-5.21 (m, 1H), 4.16 (p, J = 8.2 Hz, 1H),3.93-3.76 (m, 2H), 3.76-3.63 (m, 2H), 3.49 (q, J = 8.0 Hz, 1H), 3.38 (d,J = 11.7 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.97-2.81 (m, 2H), 2.81-2.71(m, 3H), 2.35 (s, 3H), 2.06 (s, 3H), 1.86-1.51 (m, 17H), 1.45- 1.32 (m,1H), 0.82 (d, J = 6.7 Hz, 6H).  76 761.4 ¹H NMR (400 MHz, DMSO-d6) delta9.37 (s, 1H), 0.2 8.73 (s, 1H), 8.53 (d, J = 7.7 Hz, 1H), 8.44 (s, 1H),7.88 (s, 1H), 7.71-7.64 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.54-7.47 (m,2H), 7.20 (d, J = 12.1 Hz, 1H), 5.30 (p, J = 6.5 Hz, 1H), 4.37 (hex, J =8.1 Hz, 1H), 4.18 (p, J = 8.6 Hz, 1H), 3.93-3.78 (m, 2H), 3.77- 3.66 (m,2H), 3.51 (q, J = 8.1 Hz, 1H), 3.39 (d, J = 11.8 Hz, 2H), 3.02-2.72 (m,6H), 2.36 (s, 3H), 2.23- 2.12 (m, 2H), 2.08 (s, 3H), 1.94 (p, J = 9.6Hz, 2H), 1.88-1.53 (m, 16H), 1.47-1.34 (m, 1H).  77 777.4 ¹H NMR (400MHz, DMSO-d6) delta 9.92 (d, J = 8.9 0.06 Hz, 1H), 8.62 (s, 1H), 8.36(s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.85 (s, 1H), 7.71-7.61 (m, 2H), 7.52(d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 12.2 Hz, 1H), 5.28 (p, J= 6.4 Hz, 1H), 4.17-3.98 (m, 2H), 3.96 (s, 2H), 3.93-3.80 (m, 4H),3.79-3.66 (m, 4H), 3.59- 3.46 (m, 1H), 3.07-2.81 (m, 4H), 2.34 (s, 3H),2.21- 2.05 (m, 7H), 1.87-1.73 (m, 2H), 1.69 (t, J = 5.9 Hz, 2H), 1.58(d, J = 6.5 Hz, 6H), 1.09 (d, J = 6.5 Hz, 6H).  78 777.4 ¹H NMR (400MHz, DMSO-d6) delta 9.38 (s, 1H), 0.2 8.65 (s, 1H), 8.40 (s, 1H), 8.14(d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.71-7.64 (m, 1H), 7.58 (d, J = 8.2Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.19 (d, J = 12.1 Hz,1H), 5.29 (p, J = 6.7 Hz, 1H), 4.52 (s, 2H), 4.14 (p, J = 8.4 Hz, 1H),4.04 (hex, J = 6.7 Hz, 1H), 3.93-3.79 (m, 2H), 3.79-3.57 (m, 3H), 3.38(d, J = 11.9 Hz, 2H), 3.15-2.86 (m, 4H), 2.81-2.70 (m, 2H), 2.37 (s,3H), 2.08 (s, 3H), 2.05-1.92 (m, 4H), 1.87-1.72 (m, 2H), 1.68 (t, J =5.9 Hz, 2H), 1.59 (d, J = 6.5 Hz, 6H), 1.10 (d, J = 6.5 Hz, 6H).  79618.51 ¹H NMR (400 MHz, DMSO-d6) delta 9.36 (s, 1H), 0.2 8.42 (s, 1H),8.23 (s, 1H), 8.19 (q, J = 4.6 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H),7.85-7.78 (m, 2H), 7.78 (s, 1H), 7.63 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H),7.22 (d, J = 8.3 Hz, 1H), 4.32 (p, J = 8.3 Hz, 1H), 4.15 (s, 1H), 3.53(q, J = 8.2 Hz, 2H), 3.40 (d, J = 11.8 Hz, 2H), 3.04-2.70 (m, 8H), 2.31(s, 3H), 1.83 (d, J = 14.0 Hz, 2H), 1.65 (dt, J = 40.1, 13.0 Hz, 4H),1.29 (d, J = 19.6 Hz, 10H).  80 670.3 ¹H NMR (400 MHz, Methanol-d4)delta 9.25 (s, 1H), 0.1 7.79 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 7.8, 1.6Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.61 (s, 1H), 7.44- 7.35 (m, 2H),7.30 (d, J = 8.3 Hz, 1H), 5.39 (q, J = 6.5 Hz, 1H), 4.39 (p, J = 8.2 Hz,1H), 3.88 (p, J = 7.7 Hz, 1H), 3.35 (d, J = 13.4 Hz, 1H), 2.95 (t, J =7.9 Hz, 4H), 2.91-2.85 (m, 3H), 2.43 (s, 3H), 2.18 (d, J = 12.3 Hz, 4H),2.07-1.84 (m, 2H), 1.80-1.66 (m, 8H), 1.37 (s, 6H).  81 642.3 ¹H NMR(400 MHz, Methanol-d4) delta 9.20 (s, 1H), 0.3 7.79 (s, 1H), 7.76 (dd, J= 7.8, 1.5 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H),7.44-7.36 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 5.38 (p, J = 6.6 Hz, 1H),4.41 (p, J = 8.3 Hz, 1H), 3.83 (dt, J = 11.2, 5.6 Hz, 1H), 3.75 (q, J =8.0 Hz, 1H), 3.17-2.95 (m, 4H), 2.95-2.83 (m, 7H), 2.44 (s, 3H), 1.72(d, J = 6.6 Hz, 6H), 1.38 (s, 6H).  82 626.3 ¹H NMR (400 MHz,Methanol-d4) delta 9.07 (s, 1H), 0.08 7.80-7.74 (m, 2H), 7.66 (d, J =2.4 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.30 (d, J =8.3 Hz, 1H), 5.35 (p, J = 6.4 Hz, 1H), 4.46 (p, J = 8.0 Hz, 1H), 3.81(p, J = 7.6 Hz, 1H), 3.26 (s, 1H), 3.09- 2.91 (m, 4H), 2.89 (s, 3H),2.43 (s, 3H), 1.71 (d, J = 6.6 Hz, 6H), 1.57 (s, 3H), 1.52 (s, 3H), 1.39(s, 6H).  83 731.5 ¹H NMR (400 MHz, DMSO-d6) delta 9.40 (d, J = 9.1 0.1Hz, 1H), 8.70 (s, 1H), 8.51 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.90 (s,1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.56-7.45(m, 3H), 7.18 (d, J = 8.2 Hz, 1H), 5.31 (p, J = 6.6 Hz, 1H), 4.27 (q, J= 8.3 Hz, 1H), 4.05 (dq, J = 13.8, 6.9 Hz, 1H), 3.39 (d, J = 12.2 Hz,3H), 3.02-2.73 (m, 5H), 2.31 (s, 3H), 2.08 (d, J = 3.7 Hz, 4H), 1.83 (t,J = 10.5 Hz, 4H), 1.69 (t, J = 5.8 Hz, 2H), 1.59-1.54 (m, 7H), 1.31 (d,J = 6.6 Hz, 1H), 1.10 (d, J = 6.6 Hz, 6H).  84 743.6 ¹H NMR (400 MHz,DMSO-d6) delta 9.33 (s, 1H), 0.2 8.36 (s, 1H), 8.29-8.13 (m, 2H), 7.90(d, J = 2.4 Hz, 1H), 7.88-7.79 (m, 3H), 7.66 (s, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 8.1 Hz, 1H), 4.13 (s,1H), 3.95 (s, 1H), 3.80 (d, J = 10.1 Hz, 1H), 3.06-2.71 (m, 5H), 2.32(d, J = 5.5 Hz, 4H), 1.84 (d, J = 13.8 Hz, 9H), 1.76-1.54 (m, 7H), 1.45(d, J = 19.3 Hz, 1H), 1.27 (d, J = 10.3 Hz, 5H), 1.06 (t, J = 7.2 Hz,4H).  85 757.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.42 (d, J = 0.1 10.0 Hz,1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.19 (q, J = 4.5 Hz, 1H), 7.88 (d, J =2.4 Hz, 1H), 7.86-7.79 (m, 3H), 7.66-7.61 (m, 2H), 4.88 (dd, J = 22.8,5.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (q, J = 7.2, 6.0 Hz, 3H),4.20-4.13 (m, 1H), 3.78 (d, J = 9.0 Hz, 1H), 3.61-3.47 (m, 2H), 3.40 (d,J = 11.7 Hz, 2H), 3.18 (d, J = 13.6 Hz, 1H), 3.08-2.78 (m, 4H), 2.76 (d,J = 4.6 Hz, 3H), 2.32 (s, 3H), 1.90-1.56 (m, 13H), 1.41 (d, J = 12.5 Hz,1H), 1.27 (dq, J = 4.8, 2.4 Hz, 4H).  86 765.5 ¹H NMR (400 MHz, DMSO-d6)delta 9.39 (s, 1H), 0.2 8.69 (s, 1H), 8.42 (s, 1H), 8.30 (t, J = 5.4 Hz,1H), 7.86 (s, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (d, J = 8.2 Hz,1H), 7.52-7.46 (m, 2H), 7.18 (d, J = 12.1 Hz, 1H), 5.36-5.19 (m, 1H),4.16 (t, J = 8.1 Hz, 1H), 3.94-3.76 (m, 1H), 3.71 (t, J = 6.8 Hz, 1H),3.49 (q, J = 8.1 Hz, 1H), 3.37 (tt, J = 10.1, 4.9 Hz, 7H), 3.18 (s, 3H),3.05-2.68 (m, 9H), 2.36 (s, 3H), 2.06 (s, 3H), 1.92-1.50 (m, 12H), 1.41(t, J = 12.7 Hz, 1H).  87 763.5 ¹H NMR (400 MHz, DMSO-d6) delta 9.49 (d,J = 9.7 0.3 Hz, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 8.09 (d, J = 8.4 Hz,1H), 7.88 (s, 1H), 7.64 (dd, J = 22.0, 8.0 Hz, 2H), 7.51 (d, J = 8.5 Hz,2H), 7.20 (d, J = 12.1 Hz, 1H), 5.32 (p, J = 6.6 Hz, 1H), 4.19 (p, J =8.2 Hz, 1H), 3.86 (dq, J = 13.7, 7.2 Hz, 3H), 3.73 (dt, J = 17.1, 7.9Hz, 2H), 3.53 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.02-2.73(m, 6H), 2.37 (s, 3H), 2.08 (s, 3H), 1.89-1.55 (m, 15H), 1.43 (p, J =7.5 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H).  88763.5 ¹H NMR (400 MHz, DMSO-d6) delta 9.36 (s, 1H), 0.2 8.68 (s, 1H),8.42 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.88 (s, 1H), 7.64 (dd, J =20.4, 8.3 Hz, 2H), 7.51 (dd, J = 4.6, 3.3 Hz, 2H), 7.19 (d, J = 12.1 Hz,1H), 5.30 (q, J = 6.6 Hz, 1H), 4.20 (t, J = 8.1 Hz, 1H), 3.86 (p, J =7.6 Hz, 3H), 3.79-3.64 (m, 1H), 3.52 (q, J = 8.2 Hz, 1H), 3.40 (d, J =11.6 Hz, 2H), 3.03-2.74 (m, 7H), 2.37 (s, 3H), 2.08 (s, 3H), 1.91-1.53(m, 15H), 1.43 (p, J = 7.1 Hz, 3H), 1.07 (t, J = 5.8 Hz, 3H), 0.82 (t, J= 7.4 Hz, 3H).  89 769.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.46 (s, 1H),0.2 8.77 (s, 1H), 8.69 (s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H),7.69 (dd, J = 7.8, 1.4 Hz, 1H), 7.63 (dd, J = 10.6, 9.6 Hz, 2H), 7.53(d, J = 7.9 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 5.29 (p, J = 6.6 Hz, 1H),4.20 (t, J = 8.2 Hz, 1H), 4.02 (dt, J = 7.5, 6.4 Hz, 1H), 3.94- 3.81 (m,1H), 3.73 (dq, J = 12.8, 6.2 Hz, 2H), 3.54 (q, J = 8.2 Hz, 1H), 3.41 (d,J = 11.8 Hz, 2H), 2.95 (dq, J = 28.2, 9.8 Hz, 2H), 2.78 (dd, J = 13.2,7.9 Hz, 4H), 2.08 (s, 3H), 1.92-1.52 (m, 14H), 1.41 (d, J = 12.5 Hz,1H), 1.11 (d, J = 6.6 Hz, 6H).  90 791.5 ¹H NMR (400 MHz, DMSO-d6) delta9.44 (d, J = 9.8 0.3 Hz, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H),7.88 (s, 1H), 7.66 (dd, J = 7.9, 1.5 Hz, 1H), 7.57-7.48 (m, 3H), 7.18(d, J = 12.1 Hz, 1H), 5.39-5.24 (m, 1H), 4.19 (t, J = 8.0 Hz, 1H),3.95-3.80 (m, 1H), 3.80- 3.64 (m, 2H), 3.51 (t, J = 8.1 Hz, 2H), 3.46(s, 2H), 3.39 (d, J = 11.7 Hz, 3H), 3.21 (s, 3H), 2.93 (dd, J = 25.6,10.2 Hz, 1H), 2.79 (dd, J = 12.0, 7.1 Hz, 5H), 2.35 (d, J = 0.6 Hz, 3H),2.08 (s, 3H), 1.92-1.64 (m, 5H), 1.62-1.53 (m, 7H), 1.48-1.26 (m, 1H),0.76- 0.66 (m, 4H).  91 747.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.47 (d, J= 9.1 0.1 Hz, 1H), 8.81 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 4.4 Hz, 1H),7.88 (s, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H),7.52 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 12.1Hz, 1H), 5.37-5.26 (m, 1H), 4.24-4.14 (m, 1H), 3.95-3.79 (m, 2H), 3.74(q, J = 6.4 Hz, 2H), 3.53 (dt, J = 17.1, 7.6 Hz, 1H), 3.40 (d, J = 11.9Hz, 2H), 3.00-2.86 (m, 2H), 2.86-2.73 (m, 3H), 2.37 (s, 3H), 2.08 (s,3H), 1.89-1.62 (m, 8H), 1.60 (dd, J = 6.6, 1.3 Hz, 7H), 1.48-1.29 (m,1H), 0.66 (td, J = 7.1, 4.8 Hz, 2H), 0.50-0.42 (m, 2H).  92 721.4 1H NMR(400 MHz, DMSO-d6) delta 9.42 (d, J = 0.08 9.3 Hz, 1H), 8.72 (s, 1H),8.45-8.37 (m, 1H), 8.20 (q, J = 4.5 Hz, 1H), 7.88 (s, 1H), 7.67 (dd, J =7.9, 1.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.55-7.45 (m, 2H), 7.20 (d,J = 12.2 Hz, 1H), 5.29 (p, J = 6.5 Hz, 1H), 4.23-4.11 (m, 2H), 3.95-3.79(m, 1H), 3.77- 3.66 (m, 2H), 3.51 (q, J = 8.0 Hz, 1H), 3.39 (d, J = 11.9Hz, 2H), 2.91 (dt, J = 26.9, 10.2 Hz, 2H), 2.84- 2.75 (m, 6H), 2.73 (d,J = 4.6 Hz, 3H), 2.42-2.35 (m, 3H), 2.08 (s, 3H), 1.90-1.63 (m, 8H),1.59 (d, J = 6.5 Hz, 6H).  93 739.6 1H NMR (400 MHz, DMSO-d6) delta 9.31(s, 1H), 0.2 8.70 (d, J = 8.7 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.39(s, 1H), 8.34 (d, J = 2.9 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J = 7.9, 1.5Hz, 1H), 7.65 (d, J = 11.1 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.53 (d, J= 7.8 Hz, 1H), 4.32 (t, J = 8.1 Hz, 1H), 4.15-4.03 (m, 1H), 4.02-3.79(m, 1H), 3.79-3.65 (m, 3H), 3.52 (s, 3H), 2.98 (dd, J = 26.5, 10.2 Hz,2H), 2.83 (dd, J = 18.6, 9.4 Hz, 4H), 2.77 (d, J = 4.7 Hz, 3H), 2.09 (s,3H), 1.91-1.77 (m, 3H), 1.76-1.55 (m, 5H), 1.40 (d, J = 12.8 Hz, 1H),1.32 (d, J = 3.7 Hz, 2H), 1.24 (d, J = 5.8 Hz, 3H).  94 729.5 1H NMR(400 MHz, DMSO-d6) delta 9.31 (s, 1H), 0.06 8.54 (s, 1H), 8.42 (s, 1H),8.29 (d, J = 4.5 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.63(d, J = 1.5 Hz, 1H), 7.58-7.50 (m, 2H), 7.48 (dd, J = 8.1, 2.3 Hz, 1H),7.17 (d, J = 8.4 Hz, 1H), 5.34-5.20 (m, 0H), 4.30 (t, J = 8.0 Hz, 1H),3.99-3.61 (m, 4H), 3.50 (d, J = 7.9 Hz, 2H), 3.06-2.76 (m, 9H), 2.34-2.27 (m, 3H), 2.09 (s, 3H), 1.92-1.59 (m, 10H), 1.60- 1.51 (m, 6H), 0.65(td, J = 7.1, 4.8 Hz, 2H), 0.52- 0.40 (m, 2H).  95 719.5 1H NMR (400MHz, DMSO-d6) delta 9.35 (d, J = 0.3 9.8 Hz, 1H), 8.64 (d, J = 8.5 Hz,1H), 8.42 (s, 1H), 8.23 (q, J = 4.5 Hz, 1H), 8.20 (d, J = 2.9 Hz, 1H),7.83 (d, J = 3.1 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz,1H), 7.52 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 12.4 Hz, 1H), 4.36-4.24 (m,1H), 4.09 (dt, J = 7.1, 3.3 Hz, 1H), 3.97-3.63 (m, 5H), 3.52 (d, J = 8.1Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.06-2.78 (m, 4H), 2.76 (d, J = 4.6Hz, 3H), 2.35 (s, 3H), 2.09 (s, 3H), 1.94-1.53 (m, 10H), 1.40 (d, J =12.2 Hz, 1H), 1.36-1.21 (m, 4H).  96 715.6 1H NMR (400 MHz, DMSO-d6)delta 9.30 (s, 1H), 0.2 8.36 (s, 1H), 8.19-8.13 (m, 2H), 7.88-7.83 (m,2H), 7.80 (s, 1H), 7.66 (dd, J = 4.4, 1.8 Hz, 2H), 7.56 (d, J = 7.9 Hz,1H), 4.35 (t, J = 8.2 Hz, 1H), 4.19-4.07 (m, 1H), 3.99-3.79 (m, 3H),3.62 (s, 2H), 3.40 (d, J = 12.5 Hz, 2H), 2.95-2.79 (m, 4H), 2.75 (d, J =4.6 Hz, 3H), 2.30 (s, 3H), 2.18 (s, 3H), 2.09 (s, 3H), 1.94- 1.77 (m,3H), 1.66 (d, J = 47.7 Hz, 6H), 1.40 (d, J = 12.6 Hz, 1H), 1.32-1.21 (m,4H).  97 705.3 1H NMR (400 MHz, DMSO-d6) delta 9.35 (s, 1H), 0.4 8.98(dd, J = 8.1, 2.2 Hz, 1H), 8.50 (d, J = 4.7 Hz, 1H), 8.42 (d, J = 3.2Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.88-7.78 (m, 2H), 7.64 (d, J = 1.5Hz, 1H), 7.59 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H),7.44 (dd, J = 11.0, 8.5 Hz, 1H), 4.36 (t, J = 8.2 Hz, 1H), 4.12-4.05 (m,1H), 3.98-3.68 (m, 2H), 3.37 (d, J = 12.4 Hz, 4H), 2.94 (dd, J = 30.4,10.0 Hz, 2H), 2.82 (d, J = 4.5 Hz, 4H), 2.09 (s, 4H), 1.92- 1.53 (m,11H), 1.48-1.21 (m, 5H).  98 743.1 1H NMR (400 MHz, DMSO-d6) delta 9.41(d, J = 0.09 9.6 Hz, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 8.19 (q, J = 4.6Hz, 1H), 7.89-7.81 (m, 3H), 7.80 (s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.60(d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.33 (t, J = 8.2 Hz, 1H),4.14 (dt, J = 6.6, 4.1 Hz, 1H), 3.92 (s, 5H), 3.52 (q, J = 8.1 Hz, 1H),3.40 (d, J = 11.7 Hz, 2H), 3.04-2.94 (m, 2H), 2.92-2.79 (m, 2H), 2.76(d, J = 4.6 Hz, 3H), 2.32 (s, 3H), 1.91-1.53 (m, 10H), 1.42 (t, J = 12.5Hz, 1H), 1.26 (s, 13H).  99 763.4 1H NMR (400 MHz, DMSO-d6) delta 9.78(s, 1H), 0.2 8.71 (s, 1H), 8.46 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.89(s, 1H), 7.60 (d, J = 85.2 Hz, 3H), 7.17 (d, J = 12.1 Hz, 1H), 5.37-5.23(m, 1H), 4.78 (dt, J = 23.7, 7.5 Hz, 4H), 4.24-3.93 (m, 2H), 3.43 (dd, J= 57.4, 9.9 Hz, 6H), 2.84 (dd, J = 47.9, 10.0 Hz, 6H), 2.35 (s, 3H),2.32-1.92 (m, 3H), 1.86-1.51 (m, 10H), 1.40 (t, J = 12.4 Hz, 1H), 1.09(d, J = 6.5 Hz, 5H). 100 777.4 1H NMR (400 MHz, DMSO-d6) delta 10.96 (d,J = 0.3 129.8 Hz, 2H), 8.89 (s, 1H), 8.55 (s, 1H), 8.19 (d, J = 7.8 Hz,1H), 7.97-7.38 (m, 5H), 7.19 (d, J = 12.0 Hz, 1H), 5.39-5.27 (m, 1H),4.78 (dt, J = 28.8, 7.4 Hz, 4H), 4.22-3.93 (m, 2H), 3.80-3.13 (m, 7H),2.97-2.62 (m, 3H), 2.37 (s, 3H), 2.05-1.69 (m, 2H), 1.59 (d, J = 6.5 Hz,5H), 1.16 (s, 3H), 1.13-0.99 (m, 8H). 101 624.4 1H NMR (400 MHz,DMSO-d6) delta 9.36 (s, 1H), 0.2 8.52 (s, 1H), 8.33 (s, 1H), 8.21 (q, J= 4.5 Hz, 1H), 7.83 (d, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.7Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 12.0 Hz,1H), 4.62 (q, J = 7.2 Hz, 2H), 4.17 (q, J = 8.2 Hz, 1H), 3.51 (q, J =8.2 Hz, 1H), 3.38 (d, J = 11.7 Hz, 2H), 2.91 (d, J = 10.0 Hz, 2H), 2.80(m, 4H), 2.72 (d, J = 4.5 Hz, 3), 2.37 (s, 3H), 1.83 (d, J = 14.0 Hz,2H), 1.63 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.27 (s, 6H). 102 605.4 1HNMR (400 MHz, DMSO-d6) delta 9.33 (s, 1H), 0.09 8.43 (m, 2H), 8.17 (d, J= 4.8 Hz, 1H), 7.86 (s, 1H), 7.82-7.72 (m, 1H)), 7.69-7.50 (m, 3H), 7.39(d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 4.63 (q, J = 7.1 Hz, 2H),4.27 (t, J = 8.1 Hz, 1H), 3.51 (q, J = 8.0 Hz, 1H), 3.45-3.33 (m, 2H),3.00-2.88 (m, 1H), 2.88- 2.76 (m, 3H), 2.74 (d, J = 4.5 Hz, 2H), 2.31(s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.66 (dd, J = 41.6, 13.1 Hz, 2H),1.40 (t, J = 7.2 Hz, 3H), 1.30 (s, 6H). 103 606.4 1H NMR (400 MHz,DMSO-d6) delta 10.13 (s, 1H), 0.1 8.80 (s, 1H), 8.51 (s, 1H), 8.21-8.12(m, 1H), 7.87 (s, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.65-7.47 (m,4H), 7.39 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 5.38-5.27 (m,1H), 4.38-4.25 (m, 1H), 3.73- 3.60 (m, 1H), 3.54-3.46 (m, 1H), 3.07-2.88(m, 2H), 2.85-2.71 (m, 6H), 2.32 (s, 3H), 2.07-2.02 (m, 2H), 1.94-1.86(m, 2H), 1.57 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H). 104 656.5 1H NMR (400MHz, DMSO-d6) delta 10.41 (d, J = 0.2 45.7 Hz, 1H), 8.72 (s, 1H), 8.48(s, 1H), 8.16 (q, J = 4.6 Hz, 1H), 7.87 (s, 1H), 7.77 (dd, J = 7.8, 1.4Hz, 1H), 7.57 (dd, J = 14.2, 1.9 Hz, 2H), 7.50 (dd, J = 8.2, 2.4 Hz,1H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.30 (p, J =6.5 Hz, 1H), 4.38-4.29 (m, 1H), 3.77-3.72 (m, 2H), 3.63-3.58 (m, 2H),3.20- 2.93 (m, 4H), 2.83-2.71 (m, 6H), 2.32 (s, 3H), 2.14- 2.07 (m, 1H),1.90-1.85 (m, 1H), 1.56 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H). 104A 656.3 1HNMR (400 MHz, DMSO-d6) delta 10.50 (d, J = 0.2 (1^(st) 48.1 Hz, 1H),8.91 (s, 1H), 8.55 (s, 1H), 8.21-8.12 eluting peak) (m, 1H), 7.87 (d, J= 1.2 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.60-7.55 (m, 2H), 7.51 (dd, J= 8.8, 2.1 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H),6.43-5.97 (m, 1H), 5.41-5.29 (m, 1H), 4.38- 4.29 (m, 1H), 3.75 (s, 2H),3.36-3.31 (m, 1H), 3.19- 2.89 (m, 4H), 2.83-2.77 (m, 3H), 2.77-2.71 (m,3H), 2.33 (s, 3H), 2.17-2.05 (m, 1H), 1.91-1.86 (m, 1H), 1.58 (d, J =6.4 Hz, 6H), 1.30 (s, 6H). 104B 656.3 1H NMR (400 MHz, DMSO-d6) delta10.50 (d, J = 0.2 (2^(nd) 47.4 Hz, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.16(q, J = eluting peak) 4.5 Hz, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.7 Hz,1H), 7.60-7.47 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.2 Hz,1H), 6.44-5.97 (m, 1H), 5.35 (p, J = 6.5 Hz, 1H), 4.38-4.29 (m, 1H),3.75 (s, 2H), 3.61 (s, 2H), 3.20-2.89 (m, 4H), 2.83-2.77 (m, 2H), 2.75(d, J = 4.4 Hz, 3H), 2.33 (s, 3H), 2.14-2.07 (m, 1H), 1.91-1.86 (m, 1H),1.58 (d, J = 6.4 Hz, 6H), 1.30 (s, 6H). 105 670.5 1H NMR (400 MHz,DMSO-d6) delta 9.80 (s, 1H), 0.2 8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J= 4.7 Hz, 1H), 7.91 (s, 1H), 7.81 (dd, J = 7.8, 1.4 Hz, 1H), 7.62 (d, J= 1.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.22 (d, J =8.3 Hz, 1H), 6.28-5.96 (m, 1H), 5.40-5.28 (m, 1H), 4.38-4.24 (m, 1H),3.64- 3.57 (m, 1H), 3.52-3.44 (m, 2H), 3.08-2.94 (m, 2H), 2.93-2.85 (m,4H), 2.77 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H), 2.03-1.95 (m, 1H),1.93-1.85 (m, 1H), 1.74-1.66 (m, 1H), 1.60 (dd, J = 6.6, 1.5 Hz, 6H),1.50-1.36 (m, 1H), 1.32 (s, 6H). 105A 670.4 1H NMR (400 MHz, DMSO-d6)delta 9.91 (s, 1H), 0.2 (1^(st) 8.96 (s, 1H), 8.57 (s, 1H), 8.16 (q, J =4.5 Hz, 1H), eluting peak) 7.88 (s, 1H), 7.77 (dd, J = 7.7, 1.4 Hz, 1H),7.59- 7.48 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H),6.09 (td, J = 55.6, 3.2 Hz, 1H), 5.42- 5.30 (m, 1H), 4.33-4.20 (m, 1H),3.60-3.55 (m, 0H), 3.44 (d, J = 11.4 Hz, 2H), 3.04-2.88 (m, 2H),2.90-2.78 (m, 5H), 2.74 (d, J = 4.5 Hz, 3H), 2.41- 2.36 (m, 1H), 2.33(s, 3H), 1.96 (d, J = 14.3 Hz, 1H), 1.86 (d, J = 12.8 Hz, 1H), 1.75-1.63(m, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.48-1.30 (m, 1H), 1.29 (s, 6H). 105B670.4 1H NMR (400 MHz, DMSO-d6) delta 9.70 (s, 1H), 0.09 (2^(nd) 8.72(s, 1H), 8.47 (s, 1H), 8.15 (q, J = 4.6 Hz, 1H), eluting peak) 7.88 (s,1H), 7.78 (dd, J = 7.7, 1.3 Hz, 1H), 7.59 (s, 1H), 7.57-7.47 (m, 2H),7.39 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.25-5.91 (m, 1H),5.36- 5.24 (m, 1H), 4.33-4.22 (m, 1H), 3.61-3.54 (m, 1H), 3.49-3.41 (m,2H), 3.05-2.89 (m, 2H), 2.89- 2.78 (m, 5H), 2.74 (d, J = 4.6 Hz, 3H),2.32 (s, 3H), 1.96 (d, J = 14.3 Hz, 1H), 1.86 (d, J = 12.7 Hz, 1H),1.75-1.63 (m, 1H), 1.56 (d, J = 6.4 Hz, 6H), 1.47- 1.33 (m, 1H), 1.30(s, 6H). 106 638.5 1H NMR (400 MHz, DMSO-d6) delta 9.86 (s, 1H), 0.078.85 (s, 1H), 8.53 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H), 7.76(dd, J = 7.7, 1.4 Hz, 1H), 7.58- 7.48 (m, 3H), 7.39 (d, J = 7.8 Hz, 1H),7.19 (d, J = 8.2 Hz, 1H), 5.39-5.27 (m, 1H), 5.15 (d, J = 45.4 Hz, 1H),4.30-4.21 (m, 1H), 3.70-3.47 (m, 1H), 3.41-3.10 (m, 2H), 3.04-2.90 (m,2H), 2.83 (d, J = 15.9 Hz, 3H), 2.73 (d, J = 4.5 Hz, 3H), 2.32 (s, 3H),2.03-1.94 (m, 1H), 1.91-1.76 (m, 2H), 1.74-1.66 (m, 1H), 1.57 (dd, J =6.5, 1.8 Hz, 6H), 1.29 (s, 6H). 107 656.4 1H NMR (400 MHz, DMSO-d6)delta 9.84 (s, 1H), 0.1 8.76 (s, 1H), 8.41 (s, 1H), 8.20 (q, J = 4.6 Hz,1H), 7.85 (s, 1H), 7.71-7.60 (m, 2H), 7.44 (s, 1H), 7.36 (d, J = 7.8 Hz,1H), 7.20 (d, J = 12.0 Hz, 1H), 5.30 (p, J = 6.5 Hz, 1H), 5.17 (d, J =45.0 Hz, 1H), 4.22-4.13 (m, 1H), 3.68-3.54 (m, 2H), 3.43-3.13 (m, 2H),3.03-2.90 (m, 3H), 2.85-2.70 (m, 6H), 2.38 (s, 3H), 2.04-1.95 (m, 1H),1.93-1.76 (m, 2H), 1.60 (dd, J = 6.5, 2.0 Hz, 6H), 1.28 (s, 6H). 108642.4 1H NMR (400 MHz, DMSO-d6) delta 10.70-10.44 0.1 (m, 2H), 8.60 (s,1H), 8.34 (s, 1H), 8.20 (d, J = 5.6 Hz, 1H), 7.85 (s, 1H), 7.66 (dd, J =12.9, 8.1 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H),7.25-7.16 (m, 1H), 5.64-5.41 (m, 2H), 5.30-5.22 (m, 1H), 4.28-4.23 (m,1H), 3.91-3.53 (m, 4H), 3.30-3.25 (m, 1H), 2.98-2.93 (m, 3H), 2.76-2.70(m, 3H), 2.37 (s, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.28 (s, 6H). 109 656.51H NMR (400 MHz, DMSO-d6) delta 10.68 (s, 1H), 0.3 8.71 (s, 1H), 8.36(s, 1H), 8.21 (d, J = 4.9 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J = 20.7, 8.0Hz, 2H), 7.45 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 12.4 Hz,1H), 5.61-5.56 (m, 1H), 5.48-5.43 (m, 1H), 5.13- 5.06 (m, 1H), 4.27-4.20(m, 1H), 3.94-3.54 (m, 4H), 3.41-3.15 (m, 2H), 3.01-2.88 (m, 2H), 2.73(d, J = 4.5 Hz, 3H), 2.38 (s, 3H), 2.30-2.05 (m, 1H), 2.00-1.84 (m, 2H),1.60 (d, J = 6.6 Hz, 3H), 1.28 (s, 6H), 0.82 (t, J = 7.3 Hz, 3H). 110684.5 1H NMR (400 MHz, DMSO-d6) delta 9.83 (s, 1H), 0.2 8.74 (s, 1H),8.42 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J =13.7, 7.9 Hz, 2H), 7.46 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.19 (d, J =12.0 Hz, 1H), 5.31 (p, J = 6.7 Hz, 1H), 5.25-5.08 (m, 1H), 4.22-4.15 (m,1H), 4.10-3.97 (m, 1H), 3.68-3.54 (m, 1H), 3.39 (d, J = 12.0 Hz, 1H),3.34-3.26 (m, 1H), 3.24-3.13 (m, 1H), 2.98 (q, J = 10.1 Hz, 3H), 2.80(d, J = 16.7 Hz, 3H), 2.37 (s, 3H), 2.04-1.96 (m, 1H), 1.85-1.80 (m,1H), 1.71-1.66 (m, 1H), 1.60 (d, J = 6.5 Hz, 6H), 1.28 (s, 6H), 1.10 (d,J = 6.5 Hz, 6H). 111 639.5 1H NMR (400 MHz, DMSO-d6) delta 9.46 (d, J =0.3 9.1 Hz, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.24-8.16 (m,1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.22 (d, J =11.9 Hz, 1H), 5.37- 5.26 (m, 1H), 4.29-4.17 (m, 1H), 3.59-3.48 (m, 1H),3.39 (d, J = 11.9 Hz, 2H), 2.96-2.78 (m, 7H), 2.74 (d, J = 4.5 Hz, 3H),2.39 (s, 3H), 1.85 (d, J = 14.2 Hz, 2H), 1.76-1.61 (m, 2H), 1.60 (d, J =6.5 Hz, 6H), 1.48-1.38 (m, 1H), 1.29 (s, 6H). 112 604.3 1H NMR (400 MHz,DMSO-d6) delta 9.29 (s, 1H), 0.09 8.37 (s, 1H), 8.22 (s, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.86-7.68 (m, 4H), 7.63 (d, J = 1.5 Hz, 1H), 7.45- 7.38(m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 8.1 Hz, 1H), 4.19-4.11(m, 1H), 3.40 (d, J = 11.7 Hz, 2H), 3.01-2.74 (m, 7H), 2.36 (s, 3H),1.83 (d, J = 14.2 Hz, 2H), 1.71 (d, J = 12.9 Hz, 1H), 1.60 (d, J = 13.5Hz, 2H), 1.31 (s, 6H), 1.30-1.22 (m, 4H). 113 670.4 1H NMR (400 MHz,DMSO-d6) delta 9.86 (s, 1H), 0.1 8.86 (s, 1H), 8.44 (s, 1H), 8.22 (q, J= 4.5 Hz, 1H), 7.86 (s, 1H), 7.67 (dd, J = 7.8, 1.4 Hz, 1H), 7.62 (d, J= 8.2 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 12.0Hz, 1H), 5.24-5.08 (m, 2H), 4.22- 4.13 (m, 1H), 3.71-3.54 (m, 2H),3.42-3.13 (m, 3H), 3.03-2.88 (m, 3H), 2.88-2.76 (m, 1H), 2.74 (d, J =4.6 Hz, 3H), 2.41-2.36 (m, 3H), 2.09-1.80 (m, 4H), 1.71 (d, J = 14.4 Hz,1H), 1.62 (d, J = 6.6 Hz, 3H), 1.28 (s, 6H), 0.83 (t, J = 7.4 Hz, 3H).114 654.4 1H NMR (400 MHz, DMSO-d6) delta 9.37 (d, J = 0.05 9.2 Hz, 1H),8.68 (d, J = 6.1 Hz, 2H), 8.36 (q, J = 4.6 Hz, 1H), 7.95 (s, 1H), 7.77(dd, J = 7.8, 1.4 Hz, 1H), 7.57 (ddd, J = 8.4, 4.6, 2.1 Hz, 3H),7.46-7.36 (m, 2H), 5.08 (d, J = 6.7 Hz, 1H), 4.36-4.21 (m, 1H), 3.51 (q,J = 8.0 Hz, 1H), 3.42 (d, J = 11.3 Hz, 2H), 3.37 (s, 1H), 3.03-2.88 (m,2H), 2.88-2.78 (m, 2H), 2.75 (d, J = 4.6 Hz, 3H), 1.86 (ddd, J = 14.4,10.6, 4.5 Hz, 5H), 1.77-1.52 (m, 6H), 1.50-1.35 (m, 1H), 1.30 (s, 6H),0.77 (t, J = 7.4 Hz, 3H). 115 668.3 1H NMR (400 MHz, DMSO-d6) delta 9.33(s, 1H), 0.1 8.68 (d, J = 19.1 Hz, 2H), 8.32 (d, J = 7.8 Hz, 1H), 7.93(s, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.61- 7.57 (m, 2H), 7.55 (d, J= 2.7 Hz, 1H), 7.40 (dd, J = 14.7, 8.1 Hz, 2H), 5.36-5.22 (m, 1H), 4.28(t, J = 8.1 Hz, 1H), 4.09-3.93 (m, 1H), 3.45 (dd, J = 38.2, 10.0 Hz,3H), 3.02-2.86 (m, 2H), 2.88-2.72 (m, 4H), 1.84 (d, J = 14.1 Hz, 2H),1.78-1.47 (m, 8H), 1.40 (d, J = 12.2 Hz, 1H), 1.29 (s, 6H), 1.10 (d, J =6.6 Hz, 6H). 116 682.5 1H NMR (400 MHz, DMSO-d6) delta 9.50 (s, 1H), 0.28.77 (s, 1H), 8.45 (s, 1H), 8.31 (t, J = 5.4 Hz, 1H), 7.84 (s, 1H), 7.65(dd, J = 7.8, 1.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 1.5Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 12.0 Hz, 1H), 5.38-5.23(m, 1H), 4.15 (t, J = 8.2 Hz, 1H), 3.50 (q, J = 8.1 Hz, 1H), 3.44-3.30(m, 6H), 3.18 (s, 3H), 2.97-2.69 (m, 6H), 2.36 (s, 3H), 1.89-1.52 (m,11H), 1.39 (d, J = 12.6 Hz, 1H), 1.26 (s, 6H). 117 686.4 1H NMR (400MHz, DMSO-d6) delta 9.35 (s, 1H), 0.2 8.64 (d, J = 18.0 Hz, 2H), 8.36(d, J = 7.8 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.66 (dd, J = 8.1, 5.9Hz, 2H), 7.59 (d, J = 10.8 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 7.7 Hz,1H), 5.34-5.16 (m, 1H), 4.18 (t, J = 8.2 Hz, 1H), 4.00 (q, J = 6.8 Hz,1H), 3.60-3.47 (m, 1H), 3.39 (d, J = 11.9 Hz, 2H), 2.92 (q, J = 9.8, 9.2Hz, 2H), 2.78 (d, J = 10.8 Hz, 3H), 1.83 (d, J = 14.1 Hz, 2H), 1.57 (d,J = 6.6 Hz, 10H), 1.39 (d, J = 12.8 Hz, 1H), 1.26 (s, 6H), 1.09 (d, J =6.6 Hz, 6H). 118 658.4 1H NMR (400 MHz, DMSO-d6) delta 9.31 (s, 1H),0.09 8.60 (d, J = 12.1 Hz, 2H), 8.40 (d, J = 4.7 Hz, 1H), 7.91 (s, 1H),7.72-7.64 (m, 2H), 7.60 (d, J = 10.8 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J =7.8 Hz, 1H), 5.30- 5.14 (m, 1H), 4.18 (t, J = 8.2 Hz, 1H), 3.53 (t, J =8.1 Hz, 1H), 3.39 (d, J = 11.8 Hz, 2H), 2.92 (q, J = 9.8 Hz, 2H),2.84-2.70 (m, 7H), 1.83 (d, J = 14.0 Hz, 2H), 1.56 (d, J = 6.6 Hz, 8H),1.40 (d, J = 12.5 Hz, 1H), 1.27 (s, 5H). 119 640.3 1H NMR (400 MHz,DMSO-d6) delta 9.39 (d, J = 0.07 9.2 Hz, 1H), 8.71 (d, J = 13.0 Hz, 2H),8.38 (q, J = 4.5 Hz, 1H), 7.95 (s, 1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H),7.60 (d, J = 7.8 Hz, 3H), 7.43 (dd, J = 17.8, 8.1 Hz, 3H), 5.34-5.21 (m,1H), 4.29 (t, J = 7.9 Hz, 1H), 3.52 (q, J = 8.2 Hz, 1H), 3.40 (d, J =11.8 Hz, 2H), 2.93 (dt, J = 11.5, 8.9 Hz, 2H), 2.88-2.77 (m, 4H), 2.75(d, J = 4.6 Hz, 3H), 1.85 (d, J = 14.1 Hz, 2H), 1.62 (d, J = 13.9 Hz,2H), 1.56 (d, J = 6.5 Hz, 6H), 1.43 (t, J = 12.1 Hz, 1H), 1.30 (s, 6H).120 638.4 1H NMR (400 MHz, DMSO-d6) delta 10.33 (d, J = 0.2 7.4 Hz, 1H),8.74 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 4.7 Hz, 1H), 7.85 (s, 1H),7.70-7.61 (m, 2H), 7.47 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H),7.23 (d, J = 12.0 Hz, 1H), 5.36-5.22 (m, 1H), 4.34-4.19 (m, 1H), 3.86(dt, J = 10.3, 5.3 Hz, 5H), 2.95-2.80 (m, 2H), 2.74 (d, J = 4.6 Hz, 3H),2.67 (t, J = 8.7 Hz, 2H), 2.39 (s, 3H), 1.60 (d, J = 6.5 Hz, 6H),1.43-1.23 (m, 12H). 121 646.5 1H NMR (400 MHz, DMSO-d6) delta 10.41 (d,J = 0.1 7.4 Hz, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.32 (d, J = 4.4 Hz,1H), 7.88 (s, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.60 (dd, J = 16.0,1.9 Hz, 2H), 7.46 (dd, J = 8.3, 2.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H),7.20 (d, J = 8.3 Hz, 1H), 5.41-5.25 (m, 1H), 4.40 (t, J = 8.3 Hz, 1H),3.95-3.68 (m, 7H), 2.99-2.80 (m, 3H), 2.77-2.65 (m, 3H), 2.32 (s, 3H),1.57 (d, J = 6.5 Hz, 6H), 1.44- 1.20 (m, 18H), 0.66 (td, J = 7.0, 4.7Hz, 2H), 0.52- 0.42 (m, 2H). 122 620.5 1H NMR (400 MHz, DMSO-d6) delta10.43 (d, J = 0.1 6.6 Hz, 1H), 8.78 (s, 1H), 8.52 (s, 1H), 8.18 (q, J =4.6 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.7, 1.4 Hz, 1H), 7.61 (d, J =1.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.2, 2.4 Hz, 1H),7.39 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 5.41-5.26 (m, 1H),4.37 (t, J = 8.2 Hz, 1H), 3.85 (t, J = 6.0 Hz, 5H), 2.97-2.83 (m, 2H),2.79-2.61 (m, 5H), 2.33 (s, 3H), 1.57 (d, J = 6.5 Hz, 6H), 1.40-1.21 (m,12H). 123 662.4 1H NMR (400 MHz, DMSO-d6) delta 9.45 (s, 1H), 0.1 8.51(s, 1H), 8.16 (d, J = 4.7 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.76 (dd, J= 7.9, 1.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.51 (q, J = 2.1 Hz, 2H),7.21-7.17 (m, 1H), 5.31 (d, J = 9.3 Hz, 1H), 4.24 (p, J = 8.4 Hz, 1H),4.04 (dt, J = 11.3, 5.7 Hz, 2H), 3.83 (dt, J = 10.8, 5.0 Hz, 2H), 3.47(p, J = 8.4 Hz, 1H), 3.36 (d, J = 11.7 Hz, 2H), 2.92 (q, J = 9.8 Hz,2H), 2.85-2.69 (m, 6H), 2.31 (s, 3H), 1.86-1.49 (m, 16H), 1.41 (t, J =12.3 Hz, 1H). 124 717.4 1H NMR (400 MHz, DMSO-d6) delta 9.44 (s, 1H),0.2 8.82 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.88 (d, J =0.7 Hz, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.61-7.55 (m, 2H),7.53-7.46 (m, 2H), 7.18 (d, J = 8.2 Hz, 1H), 5.33 (s, 1H), 4.26 (p, J =8.3 Hz, 1H), 4.02 (tt, J = 9.2, 6.3 Hz, 3H), 3.83 (dt, J = 10.9, 5.1 Hz,2H), 3.52-3.31 (m, 3H), 2.92 (q, J = 10.0, 9.6 Hz, 2H), 2.78 (q, J =10.6, 8.8 Hz, 4H), 2.30 (s, 3H), 1.90-1.47 (m, 15H), 1.41 (t, J = 12.6Hz, 1H), 1.08 (d, J = 6.6 Hz, 6H). 125 708.4 1H NMR (400 MHz, DMSO-d6)delta 9.50 (s, 1H), 0.2 8.87 (s, 1H), 8.50 (s, 1H), 8.15 (d, J = 7.9 Hz,1H), 7.85 (s, 1H), 7.65 (dd, J = 7.9, 1.4 Hz, 1H), 7.56 (dd, J = 8.0,5.2 Hz, 2H), 7.46 (d, J = 1.4 Hz, 1H), 7.19 (d, J = 12.1 Hz, 1H), 5.32(p, J = 6.7 Hz, 1H), 4.16 (p, J = 8.3 Hz, 1H), 4.03 (ddd, J = 13.5, 6.4,4.6 Hz, 3H), 3.81 (dt, J = 10.9, 5.1 Hz, 2H), 3.50 (h, J = 8.5 Hz, 1H),3.38 (d, J = 11.7 Hz, 2H), 2.98-2.85 (m, 2H), 2.85-2.70 (m, 4H), 2.36(s, 3H), 1.89-1.52 (m, 15H), 1.39 (q, J = 13.0, 12.6 Hz, 1H), 1.08 (d, J= 6.6 Hz, 6H). 126 646.4 1H NMR (400 MHz, CDCl3) delta 8.16 (d, 1H),7.87 0.07 (d, 1H), 7.73 (m, 1H), 7.63 (m, 3H), 7.51 (d, 1H), 7.41 (m,1H), 7.16 (m, 1H), 6.49 (s, 1H), 6.24 (s, 1H), 4.40 (p, 1H), 4.21 (m,2H), 3.92 (m, 3H), 3.76 (m, 1H), 3.04 (d, 2H), 2.72 (m, 6H), 2.47 (m,3H), 1.84 (m, 10H), 1.52 (m, 3H), 1.32 (m, 5H). 127 660.5 1H NMR (400MHz, DMSO) delta 9.41 (s, 1H), 8.43 0.1 (s, 1H), 8.23 (s, 1H), 8.19 (q,1H), 7.91 (d, 1H), 7.80 (m, 4H), 7.61 (m, 2H), 7.21 (d, 1H), 4.31 (p,1H), 4.08 (m, 3H), 3.84 (m, 3H), 3.44 (m, 4H), 2.96 (m, 2H), 2.83 (m,4H), 2.75 (d, 3H), 2.30 (s, 3H), 1.71 (m, 12H), 1.40 (t, 1H), 1.26 (m,5H). 128 634.5 1H NMR (400 MHz, DMSO-d6) delta 9.40 (d, J = 0.1 10.0 Hz,1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.14 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H),7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.60-7.27 (m, 4H), 7.17 (d, J = 8.3 Hz,1H), 5.10 (q, J = 6.6 Hz, 1H), 4.24 (p, J = 8.3 Hz, 1H), 3.42 (dt, J =47.2, 9.5 Hz, 4H), 3.03-2.63 (m, 10H), 2.30 (s, 3H), 2.04-1.11 (m, 15H),0.77 (t, J = 7.4 Hz, 3H). 129 749.4 1H NMR (400 MHz, DMSO-d6) delta 9.47(s, 1H), 0.2 8.85 (s, 1H), 8.49 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.86(d, J = 0.9 Hz, 1H), 7.64 (dd, J = 7.9, 1.5 Hz, 1H), 7.56 (d, J = 8.2Hz, 1H), 7.53-7.45 (m, 2H), 7.18 (d, J = 12.0 Hz, 1H), 5.38-5.25 (m,1H), 4.16 (t, J = 8.1 Hz, 1H), 4.02 (dq, J = 13.6, 6.7 Hz, 1H),3.93-3.76 (m, 1H), 3.70 (p, J = 7.7, 7.1 Hz, 2H), 3.49 (p, J = 8.3 Hz,1H), 3.38 (d, J = 11.7 Hz, 2H), 3.00-2.71 (m, 7H), 2.35 (d, J = 0.8 Hz,3H), 2.06 (s, 3H), 1.86-1.53 (m, 13H), 1.40 (t, J = 12.5 Hz, 1H), 1.08(d, J = 6.6 Hz, 6H). 130 717.62 1H NMR (400 MHz, DMSO-d6) delta 9.53 (d,J = 0.1 12.8 Hz, 1H), 8.88 (d, J = 9.8 Hz, 1H), 8.58 (d, J = 4.7 Hz,1H), 8.25 (t, J = 5.7 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H),7.60 (s, 1H), 7.58-7.47 (m, 3H), 7.20 (d, J = 8.1 Hz, 1H), 5.34 (dq, J =13.0, 6.8, 5.3 Hz, 1H), 4.26 (p, J = 8.3 Hz, 1H), 3.49 (q, J = 8.1 Hz,1H), 3.38 (d, J = 11.6 Hz, 2H), 3.23 (p, J = 7.0 Hz, 2H), 3.02-2.72 (m,7H), 2.32 (s, 3H), 2.08 (s, 3H), 1.90-1.76 (m, 4H), 1.76-1.63 (m, 3H),1.57 (d, J = 6.4 Hz, 6H), 1.50-1.35 (m, 1H), 1.06 (t, J = 7.2 Hz, 3H).131 747.54 1H NMR (400 MHz, DMSO-d6) delta 9.39 (d, J = 0.2 9.8 Hz, 1H),8.75 (s, 1H), 8.53 (s, 1H), 8.27 (t, J = 5.4 Hz, 1H), 7.90 (s, 1H), 7.77(dd, J = 7.9, 1.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.57-7.46 (m, 3H),7.19 (d, J = 8.3 Hz, 1H), 5.37-5.26 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H),3.39 (dt, J = 14.1, 5.3 Hz, 6H), 3.19 (s, 3H), 2.93 (dd, J = 25.7, 10.2Hz, 1H), 2.81 (t, J = 9.7 Hz, 5H), 2.32 (s, 3H), 2.09 (s, 4H), 1.88-1.76(m, 3H), 1.75-1.61 (m, 3H), 1.57 (dd, J = 6.5, 1.5 Hz, 7H). 132 733.521H NMR (400 MHz, DMSO-d6) delta 9.43 (d, J = 0.1 10.1 Hz, 1H), 8.78 (d,J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.18 (t, J = 5.7 Hz, 1H), 7.90 (s, 1H),7.77 (dd, J = 7.9, 1.4 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.57-7.45 (m,3H), 7.20 (d, J = 8.2 Hz, 1H), 5.32 (p, J = 6.5 Hz, 1H), 4.32-4.21 (m,1H), 3.47 (t, J = 6.4 Hz, 2H), 3.38 (d, J = 11.7 Hz, 2H), 3.29 (q, J =6.2 Hz, 2H), 2.93 (dd, J = 25.1, 10.3 Hz, 2H), 2.81 (td, J = 10.4, 9.4,5.5 Hz, 4H), 2.54 (s, 0H), 2.33 (s, 3H), 2.08 (d, J = 3.7 Hz, 4H), 1.82(tt, J = 9.9, 4.8 Hz, 4H), 1.70 (q, J = 8.2, 6.2 Hz, 3H), 1.57 (d, J =6.5 Hz, 8H), 1.43 (dd, J = 14.7, 10.4 Hz, 1H). 133 608.2 1H NMR (400MHz, DMSO-d6) delta 8.78 (s, 1H), 0.9 8.49 (s, 1H), 7.84 (s, 1H),7.77-7.67 (m, 3H), 7.64 (dd, J = 8.0, 2.1 Hz, 2H), 7.59 (d, J = 2.4 Hz,1H), 7.41-7.35 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 4.69 (q, J = 7.2 Hz,2H), 4.13 (dt, J = 22.5, 7.9 Hz, 2H), 2.77- 2.61 (m, 3H), 2.35 (s, 3H),1.45 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H), 1.15 (d, J = 0.6 Hz, 1H), 1.10(d, J = 0.6 Hz, 9H).; 1H NMR (400 MHz, DMSO-d6) delta 9.09 (s, 1H), 8.96(s, 1H), 7.70 (dd, J = 7.3, 2.3 Hz, 1H), 7.66 (dt, J = 8.5, 2.5 Hz, 2H),7.57-7.48 (m, 2H), 7.45 (d, J = 2.3 Hz, 1H), 7.37-7.27 (m, 2H), 7.11 (d,J = 2.4 Hz, 1H), 7.07 (dd, J = 8.4, 2.3 Hz, 1H), 4.33- 4.21 (m, 1H),4.13-3.96 (m, 3H), 2.72 (dt, J = 9.6, 4.8 Hz, 4H), 2.27 (d, J = 2.4 Hz,3H), 1.35 (d, J = 2.4 Hz, 6H), 1.10 (t, J = 2.3 Hz, 1H), 1.03 (d, J =2.5 Hz, 8H), 0.97 (td, J = 7.2, 2.3 Hz, 3H). 134 697.3 1H NMR (400 MHz,DMSO-d6) δ 9.42 (d, J = 9.2 0.3 Hz, 1H), 8.75-8.66 (m, 3H), 8.46 (s,1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.21 (d, J =12.0 Hz, 1H), 5.37-5.25 (m, 1H), 4.54 (s, 1H), 4.42 (s, 1H), 4.31-4.18(m, 1H), 3.58-3.45 (m, 1H), 3.40 (d, J = 11.9 Hz, 2H), 2.97-2.74 (m,6H), 2.36 (s, 3H), 1.85 (d, J = 14.2 Hz, 2H), 1.76-1.62 (m, 2H), 1.60(d, J = 6.4 Hz, 6H), 1.48-1.37 (m, 1H), 1.29 (s, 6H), 0.92-0.78 (m, 4H).135 622.4 1H NMR (400 MHz, DMSO-d6) delta 9.04 (s, 1H), 0.6 8.56 (s,1H), 7.82 (s, 1H), 7.74-7.65 (m, 3H), 7.62 (d, J = 1.5 Hz, 1H), 7.58(dd, J = 8.2, 2.4 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.40-7.32 (m, 2H),7.18 (d, J = 8.3 Hz, 1H), 5.37 (p, J = 6.5 Hz, 1H), 4.18-4.02 (m, 2H),2.75-2.56 (m, 2H), 2.33 (s, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.26 (s, 6H),1.08 (s, 9H). 136 648.4 1H NMR (400 MHz, Methanol-d4) delta 9.26 (s, 0.11H), 7.79 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.74 (d, J = 2.4 Hz,1H), 7.65 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d,J = 7.8 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H),4.43-4.31 (m, 1H), 4.16 (p, J = 6.6 Hz, 1H), 3.63 (p, J = 8.1 Hz, 1H),3.52 (d, J = 12.3 Hz, 2H), 3.05 (dt, J = 11.6, 8.9 Hz, 2H), 2.98-2.80(m, 4H), 2.43 (s, 3H), 2.00 (d, J = 14.5 Hz, 2H), 1.88 (d, J = 13.6 Hz,1H), 1.73 (d, J = 6.5 Hz, 8H), 1.57 (t, J = 12.9 Hz, 1H), 1.38 (s, 6H),1.18 (d, J = 6.6 Hz, 6H). 137 664.4 1H NMR (400 MHz, Methanol-d4) delta9.18 (d, J = 0.1 2.4 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.75 (dd, J =7.9, 1.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H),7.44-7.35 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 5.37 (p, J = 7.0 Hz, 1H),4.36 (p, J = 8.0 Hz, 1H), 3.64 (p, J = 8.2 Hz, 1H), 3.51 (p, J = 3.9,3.2 Hz, 6H), 3.25 (s, 3H), 3.03 (dt, J = 11.8, 9.2 Hz, 2H), 2.97-2.79(m, 4H), 2.44 (d, J = 2.9 Hz, 3H), 2.00 (d, J = 14.5 Hz, 2H), 1.87 (d, J= 13.0 Hz, 1H), 1.71 (dd, J = 7.0, 2.5 Hz, 8H), 1.57 (t, J = 13.0 Hz,1H), 1.37 (s, 6H). 138 634.4 1H NMR (400 MHz, Methanol-d4) delta 9.25(s, 0.1 1H), 7.79 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.71 (d, J =2.4 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.2, 2.4 Hz, 1H),7.40 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 5.39 (p, J = 6.6 Hz,1H), 4.43-4.29 (m, 1H), 3.68-3.56 (m, 1H), 3.52 (d, J = 12.2 Hz, 2H),3.37 (q, J = 7.3 Hz, 2H), 3.05 (qd, J = 9.1, 2.8 Hz, 2H), 2.97-2.79 (m,4H), 2.44 (s, 3H), 2.00 (d, J = 14.2 Hz, 2H), 1.90 (s, 2H), 1.76 (m,1H), 1.73 (d, J = 6.6 Hz, 6H), 1.56 (q, J = 12.7 Hz, 1H), 1.38 (s, 6H),1.16 (t, J = 7.2 Hz, 3H). 139 662.4 1H NMR (400 MHz, Methanol-d4) delta9.30 (s, 0.06 1H), 7.81-7.78 (m, 2H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H),7.65 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.2, 2.4 Hz, 1H), 7.39 (d, J =7.8 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 5.42 (p, J = 6.6 Hz, 1H), 4.34(p, J = 8.1 Hz, 1H), 3.62 (p, J = 8.1 Hz, 1H), 3.52 (d, J = 12.3 Hz,2H), 3.16 (dd, J = 6.7, 4.8 Hz, 2H), 3.03 (qd, J = 9.2, 2.7 Hz, 2H),2.97-2.79 (m, 4H), 2.44 (s, 3H), 2.04- 1.67 (m, 12H), 1.57 (t, J = 12.7Hz, 1H), 1.38 (s, 6H), 0.88 (d, J = 6.7 Hz, 6H). 140 690.3 1H NMR (400MHz, Methanol-d4) delta 8.83 (s, 0.3 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.84(s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.64 (s, 1H), 7.53 (dd, J =8.9, 2.8 Hz, 1H), 7.40-7.34 (m, 2H), 5.38-5.25 (m, 1H), 4.46-4.34 (m,1H), 3.67-3.48 (m, 3H), 3.15-3.02 (m, 2H), 2.98-2.71 (m, 7H), 2.05-1.70(m, 5H), 1.67 (d, J = 6.6 Hz, 6H), 1.60-1.51 (m, 1H), 1.37 (s, 6H). 141674 1H NMR (400 MHz, Methanol-d4) delta 8.51 (s, 0.07 1H), 7.90 (s, 1H),7.83-7.69 (m, 2H), 7.64 (s, 2H), 7.51 (s, 1H), 7.37-7.32 (m, 1H),5.28-5.12 (m, 1H), 4.31-4.22 (m, 1H), 3.74-3.48 (m, 1H), 2.86 (s, 3H),2.75-2.55 (m, 4H), 2.50-2.30 (m, 4H), 1.71-1.42 (m, 12H), 1.35 (s, 6H).142 646 1H NMR (400 MHz, Methanol-d4) delta 8.44 (s, 0.2 1H), 7.81-7.72(m, 3H), 7.48-7.41 (m, 2H), 7.37- 7.28 (m, 1H), 7.00 (d, J = 8.5 Hz,1H), 5.25-5.11 (m, 1H), 4.38-4.24 (m, 1H), 3.05-2.84 (m, 4H), 2.82-2.43(m, 8H), 2.27-2.10 (m, 1H), 1.71-1.49 (m, 12H), 1.35 (s, 6H), 0.99-0.85(m, 2H), 0.78- 0.61 (m, 2H). 143 634 1H NMR (400 MHz, Methanol-d4) delta9.15 (s, 0.06 1H), 7.82-7.75 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.64 (d,J = 1.5 Hz, 1H), 7.48-7.39 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 5.42-5.33(m, 1H), 4.44-4.34 (m, 1H), 3.73-3.62 (m, 1H), 3.58-3.48 (m, 2H), 3.18-3.02 (m, 2H), 3.00-2.78 (m, 9H), 2.06-1.52 (m, 12H), 1.40 (s, 6H), 1.27(t, J = 7.6 Hz, 3H). 144 732.4 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d,J = 3.1 0.07 Hz, 2H), 7.82 (s, 1H), 7.71 (td, J = 7.6, 1.6 Hz, 2H), 7.55(d, J = 1.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 5.93 (t, J = 57.1 Hz,1H), 5.36 (p, J = 6.6 Hz, 1H), 4.37 (p, J = 8.4 Hz, 1H), 3.67 (p, J =8.2 Hz, 1H), 3.57 (d, J = 12.4 Hz, 2H), 3.18-3.06 (m, 2H), 3.00- 2.82(m, 4H), 2.40 (d, J = 2.3 Hz, 3H), 2.03 (d, J = 17.2 Hz, 2H), 1.91 (d, J= 13.1 Hz, 1H), 1.84-1.67 (m, 8H), 1.59 (t, J = 12.9 Hz, 1H), 1.40 (s,6H), 1.21- 1.12 (m, 2H), 1.00-0.89 (m, 2H). 145 744.4 1H NMR (400 MHz,DMSO-d6) δ 9.91-9.31 (m, 0.07 1H), 8.96 (s, 1H), 8.70-8.56 (m, 2H), 7.88(s, 1H), 7.67-7.60 (m, 1H), 7.45-7.32 (m, 3H), 6.04 (t, J = 56.9 Hz,1H), 5.27 (p, J = 6.6 Hz, 1H), 4.24-4.07 (m, 2H), 3.97 (s, 1H),3.75-3.52 (m, 1H), 3.42-3.20 (m, 1H), 3.07-2.72 (m, 5H), 2.71-2.60 (m,1H), 2.29 (s, 3H), 2.02-1.87 (m, 1H), 1.84-1.48 (m, 10H), 1.46-1.34 (m,1H), 1.28 (s, 6H), 1.15-1.01 (m, 2H), 0.93-0.85 (s, 2H). 146 747.4 1HNMR (400 MHz, DMSO-d6) delta 9.36 (d, J = 0.1 9.2 Hz, 1H), 8.69 (s, 1H),8.47 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H), 7.90 (s, 1H), 7.79 (dd, J = 7.9,1.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.56-7.48 (m, 3H), 7.23-7.15 (m,1H), 5.36-5.20 (m, 1H), 4.28 (t, J = 8.3 Hz, 1H), 3.57-3.45 (m, 1H),3.39 (d, J = 11.8 Hz, 2H), 2.94 (d, J = 10.3 Hz, 2H), 2.82 (t, J = 9.8Hz, 3H), 2.73 (d, J = 4.6 Hz, 3H), 2.32 (s, 3H), 1.89- 1.67 (m, 9H),1.62 (d, J = 13.3 Hz, 2H), 1.56 (d, J = 6.5 Hz, 6H), 1.47 (s, 1H), 1.42(s, 1H), 1.37 (s, 6H), 1.30 (s, 1H). 147 733.4 1H NMR (400 MHz, DMSO-d6)delta 9.38 (s, 1H), 0.2 8.70 (s, 1H), 8.48 (s, 1H), 8.16 (q, J = 4.5 Hz,1H), 7.90 (d, J = 2.6 Hz, 1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H), 7.65-7.56(m, 2H), 7.52 (d, J = 5.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 5.29 (q, J= 6.5 Hz, 1H), 4.50 (q, J = 6.5 Hz, 1H), 4.28 (t, J = 8.2 Hz, 1H), 3.88(s, 5H), 3.58-3.44 (m, 1H), 3.39 (d, J = 12.0 Hz, 3H), 2.94 (dd, J =20.1, 10.0 Hz, 2H), 2.81 (t, J = 9.7 Hz, 3H), 2.74 (d, J = 4.6 Hz, 3H),2.32 (s, 3H), 1.91- 1.67 (m, 8H), 1.62 (d, J = 7.0 Hz, 0H), 1.56 (d, J =6.5 Hz, 6H), 1.49-1.35 (m, 1H), 1.31 (s, 1H), 1.24 (t, J = 7.1 Hz, 3H).148 771.4 1H NMR (400 MHz, DMSO-d6) delta 9.46 (d, J = 0.2 9.6 Hz, 1H),8.80 (s, 1H), 8.52 (s, 1H), 8.17 (q, J = 4.5 Hz, 1H), 7.90 (s, 1H), 7.77(dd, J = 7.9, 1.5 Hz, 1H), 7.63-7.56 (m, 2H), 7.55-7.49 (m, 2H), 7.20(d, J = 8.2 Hz, 1H), 5.41-5.26 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H),3.99-3.69 (m, 4H), 3.50 (q, J = 8.1 Hz, 1H), 3.38 (d, J = 11.7 Hz, 2H),3.03-2.77 (m, 7H), 2.74 (d, J = 4.6 Hz, 3H), 2.32 (s, 3H), 2.13 (s, 6H),1.84 (d, J = 13.9 Hz, 2H), 1.70 (dd, J = 15.1, 9.6 Hz, 6H), 1.57 (d, J =6.5 Hz, 6H), 1.42 (d, J = 12.7 Hz, 1H). 149 755.1 1H NMR (400 MHz,DMSO-d6) delta 9.40 (d, J = 0.1 9.4 Hz, 1H), 8.43 (s, 1H), 8.24 (s, 1H),8.19 (q, J = 4.5 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.83 (td, J = 8.3,1.9 Hz, 2H), 7.80 (s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.33 (t, J = 8.2 Hz, 1H), 4.20-4.10(m, 1H), 3.59-3.46 (m, 2H), 3.40 (d, J = 12.0 Hz, 4H), 2.84 (dd, J =25.7, 10.5 Hz, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.32 (s, 3H), 2.02-1.90(m, 1H), 1.89-1.53 (m, 13H), 1.41 (s, 5H), 1.27 (dq, J = 7.1, 2.2 Hz,5H). 150 741.4 1H NMR (400 MHz, DMSO-d6) delta 9.56 (d, J = 0.1 9.8 Hz,1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.20 (q, J = 4.6 Hz, 1H), 7.91-7.78 (m,4H), 7.68-7.58 (m, 2H), 7.24 (d, J = 8.2 Hz, 1H), 4.32 (p, J = 8.3 Hz,1H), 4.24 -4.16 (m, 1H), 3.93 (s, 4H), 3.58-3.48 (m, 1H), 3.39 (d, J =11.8 Hz, 2H), 3.06-2.92 (m, 2H), 2.93- 2.79 (m, 2H), 2.76 (d, J = 4.6Hz, 3H), 2.32 (s, 3H), 1.71 (dq, J = 60.8, 13.8 Hz, 11H), 1.43 (t, J =12.5 Hz, 1H), 1.29 (d, J = 3.9 Hz, 6H), 0.88 (d, J = 4.9 Hz, 2H),0.62-0.51 (m, 2H). 151 731.55 1H NMR (400 MHz, DMSO-d6) delta 8.43 (d, J= 0.05 2.6 Hz, 1H), 8.24 (s, 1H), 8.19 (q, J = 4.6 Hz, 1H), 7.91 (dd, J= 10.9, 2.3 Hz, 1H), 7.82 (dd, J = 13.7, 5.0 Hz, 3H), 7.65 (s, 1H), 7.57(d, J = 35.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.51 (q, J = 6.5 Hz,1H), 4.33 (p, J = 8.2 Hz, 1H), 4.14 (td, J = 6.6, 3.2 Hz, 1H), 3.89 (d,J = 21.1 Hz, 2H), 3.04-2.78 (m, 5H), 2.76 (d, J = 4.5 Hz, 3H), 2.32 (s,3H), 1.84 (d, J = 14.5 Hz, 3H), 1.78-1.67 (m, 2H), 1.62 (d, J = 13.4 Hz,2H), 1.48- 1.35 (m, 1H), 1.30-1.21 (m, 8H). 152 743.5 1H NMR (400 MHz,DMSO-d6) delta 9.45 (d, J = 0.2 9.4 Hz, 1H), 8.85 (s, 1H), 8.54 (s, 1H),8.17 (d, J = 4.7 Hz, 1H), 7.91 (s, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H),7.60 (d, J = 7.7 Hz, 2H), 7.56-7.50 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H),5.41-5.27 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H), 3.92 (s, 4H), 3.51 (q, J =8.1 Hz, 1H), 3.38 (d, J = 11.8 Hz, 2H), 2.94 (q, J = 9.7 Hz, 2H), 2.80(d, J = 11.1 Hz, 4H), 2.74 (d, J = 4.6 Hz, 3H), 2.32 (s, 3H), 1.88-1.61(m, 9H), 1.58 (d, J = 6.5 Hz, 6H), 1.42 (d, J = 12.4 Hz, 1H), 1.28 (s,3H), 0.93-0.83 (m, 2H), 0.61-0.54 (m, 2H). 153 743.4 1H NMR (400 MHz,DMSO-d6) delta 9.50 (d, J = 0.1 9.5 Hz, 1H), 8.47 (s, 1H), 8.26 (s, 1H),8.20 (q, J = 4.5 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.87-7.78 (m, 3H),7.64 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.4 Hz,1H), 4.84-4.68 (m, 4H), 4.32 (t, J = 8.1 Hz, 1H), 4.25-4.12 (m, 2H),4.07- 3.92 (m, 1H), 3.86-3.71 (m, 1H), 3.71-3.59 (m, 1H), 3.52 (q, J =8.1 Hz, 1H), 3.40 (d, J = 11.9 Hz, 4H), 3.07-2.79 (m, 2H), 2.76 (d, J =4.6 Hz, 4H), 2.32 (s, 3H), 1.90-1.53 (m, 11H), 1.41 (d, J = 12.7 Hz,1H), 1.27 (tt, J = 4.1, 2.1 Hz, 4H). 154 771 1H NMR (400 MHz, DMSO-d6)delta 9.36 (d, J = 0.06 9.7 Hz, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 8.19(q, J = 4.5 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.83 (ddd, J = 7.6, 5.6,2.0 Hz, 2H), 7.80 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 7.9Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (d, J = 8.1 Hz, 1H), 4.19-4.09(m, 1H), 3.97-3.74 (m, 5H), 3.52 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8Hz, 2H), 2.86 (dt, J = 26.8, 12.9 Hz, 5H), 2.76 (d, J = 4.6 Hz, 3H),2.45 (d, J = 2.5 Hz, 6H), 2.32 (s, 3H), 1.89-1.55 (m, 9H), 1.41 (d, J =12.7 Hz, 1H), 1.27 (d, J = 8.6 Hz, 4H). 155 741.2 1H NMR (400 MHz,DMSO-d6) delta 9.34 (s, 1H), 0.06 8.40 (s, 1H), 8.23 (s, 1H), 8.18 (t, J= 4.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.85-7.80 (m, 2H), 7.80 (s,1H), 7.65 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.24-7.20 (m,1H), 4.33 (t, J = 8.2 Hz, 1H), 4.19-4.08 (m, 1H), 3.83 (d, J = 44.5 Hz,5H), 3.66- 3.46 (m, 2H), 3.42 (dd, J = 17.4, 9.2 Hz, 3H), 3.09- 2.79 (m,5H), 2.76 (d, J = 4.6 Hz, 3H), 2.31 (s, 3H), 2.29-2.05 (m, 3H),1.99-1.54 (m, 10H), 1.41 (d, J = 12.6 Hz, 1H), 1.27 (d, J = 8.9 Hz, 5H).156 753.6 1H NMR (400 MHz, DMSO-d6) delta 9.34 (s, 1H), 0.06 8.39 (s,1H), 8.23 (s, 1H), 8.18 (q, J = 4.5 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H),7.86-7.80 (m, 2H), 7.80 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.59 (d, J =7.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (q, J = 8.3 Hz, 1H),4.17-4.10 (m, 1H), 4.05-3.71 (m, 6H), 3.52 (q, J = 8.1 Hz, 1H), 3.40 (d,J = 11.8 Hz, 2H), 3.08- 2.79 (m, 5H), 2.76 (d, J = 4.6 Hz, 3H), 2.32 (s,3H), 2.14 (s, 6H), 1.90-1.55 (m, 9H), 1.41 (d, J = 12.8 Hz, 1H), 1.27(d, J = 8.9 Hz, 4H). 157 735 1H NMR (400 MHz, Methanol-d4) delta 8.98(s, 0.2 1H), 7.80 (s, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (s, 1H),7.60 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.3,2.4 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.17-5.09 (m, 2H), 4.44-4.36 (m,1H), 4.12-3.99 (m, 3H), 3.91-3.52 (m, 4H), 3.18-2.93 (m, 6H), 2.87 (s,3H), 2.41 (s, 3H), 2.19 (s, 3H), 2.09- 1.83 (m, 10H), 1.71-1.67 (m, 3H),0.97-0.92 (m, 3H). 158 765 1H NMR (400 MHz, Methanol-d4) delta 8.45 (s,0.2 1H), 7.83-7.68 (m, 3H), 7.50-7.34 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H),5.03-4.93 (m, 1H), 4.38-4.26 (m, 1H), 4.09-3.77 (m, 4H), 3.09-2.95 (m,1H), 2.93-2.54 (m, 11H), 2.38 (s, 3H), 2.24-2.11 (m, 4H), 2.04-1.76 (m,7H), 1.62 (d, J = 6.7 Hz, 3H), 1.44-1.26 (m, 2H), 0.85 (t, J = 7.4 Hz,3H). 159 715 1H NMR (400 MHz, Methanol-d4) delta 8.61 (s, 0.1 1H), 8.16(d, J = 2.4 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.65 (s,1H), 7.58 (dd, J = 8.2, 2.4 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.27 (d,J = 8.4 Hz, 1H), 4.45-4.43 (m, 1H), 4.13-4.02 (m, 3H), 3.94- 3.81 (m,3H), 3.75-3.67 (m, 1H), 3.50-3.35 (m, 2H), 3.17-3.08 (m, 2H), 3.00-2.92(m, 3H), 2.89 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H), 1.98-1.83 (m, 6H),1.45-1.35 (m, 4H), 1.30-1.18 (m, 6H). 160 757 1H NMR (400 MHz,Methanol-d4) delta 8.72 (s, 0.08 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.83 (d,J = 8.4 Hz, 1H), 7.73 (d, J = 1.4 Hz, 1H), 7.66 (s, 1H), 7.59- 7.50 (m,2H), 7.28 (d, J = 8.3 Hz, 1H), 4.67-4.59 (m, 1H), 4.22-4.14 (m, 1H),4.12-4.06 (m, 1H), 4.02-3.96 (m, 1H), 3.94-3.68 (m, 4H), 3.38-3.34 (m,1H), 3.24-3.17 (m, 2H), 3.08-3.00 (m, 2H), 2.89 (s, 3H), 2.65 (d, J =12.4 Hz, 2H), 2.41 (s, 3H), 2.20 (s, 3H), 2.06-1.87 (m, 5H), 1.65-1.58(m, 1H), 1.47-1.39 (m, 4H), 1.32 (d, J = 3.1 Hz, 6H), 1.07 (s, 6H). 161729 1H NMR (400 MHz, Methanol-d4) delta 8.24 (s, 0.06 1H), 7.99 (s, 1H),7.85-7.73 (m, 3H), 7.59 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.23 (d, J =8.4 Hz, 1H), 4.47-4.37 (m, 2H), 4.21-3.70 (m, 7H), 2.95-2.65 (m, 9H),2.39 (s, 3H), 2.19 (s, 3H), 1.95-1.84 (m, 2H), 1.86-1.79 (m, 2H),1.70-1.60 (m, 2H), 1.42- 1.25 (m, 6H), 1.00-0.85 (s, 6H). 162 721 1H NMR(400 MHz, Methanol-d4) delta 8.47 (s, 0.1 1H), 7.84-7.74 (m, 2H), 7.69(s, 1H), 7.60 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.2, 2.3Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 5.25-5.13 (m, 2H), 4.43-4.34 (m, 1H),4.11-3.52 (m, 8H), 3.08-2.78 (m, 7H), 2.39 (s, 3H), 2.19 (s, 3H),2.10-1.78 (m, 8H), 1.63 (d, J = 6.6 Hz, 6H). 163 764 1H NMR (400 MHz,Methanol-d4) delta 8.22 (s, 0.1 1H), 7.93-7.81 (m, 3H), 7.76 (dd, J =7.9, 1.5 Hz, 1H), 7.60 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.23 (d, J =8.4 Hz, 1H), 4.42-4.29 (m, 1H) 4.09-3.78 (m, 5H), 2.89 (s, 3H),2.82-2.57 (m, 5H), 2.55-2.41 (m, 3H), 2.39 (s, 3H), 2.36-2.29 (m, 1H),2.18 (s, 3H), 1.93-1.86 (m, 2H), 1.85-1.78 (m, 2H), 1.74-1.46 (m, 4H),1.40-1.26 (m, 4H), 1.17-1.04 (m, 2H). 164 751 1H NMR (400 MHz,Methanol-d4) delta 8.82 (s, 0.2 1H), 7.80-7.73 (m, 2H), 7.69-7.60 (m,2H), 7.52- 7.47 (m, 1H), 7.39-7.34 (m, 1H), 7.29-7.21 (m, 1H), 5.33-5.26(m, 1H), 4.48-4.40 (m, 1H), 4.14- 3.98 (m, 3H), 3.95-3.82 (m, 3H),3.76-3.44 (ms, 3H), 3.25-3.10 (m, 3H), 2.95-2.85 (m, 5H), 2.41 (s, 34H),2.19 (s, 3H), 1.96-1.88 (m, 2H), 1.87-1.80 (m, 2H), 1.76-1.63 (m, 8H).165 716 1H NMR (400 MHz, Methanol-d4) delta 9.23 (s, 0.1 1H), 7.83-7.72(m, 2H), 7.64 (dd, J = 11.5, 1.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 1H), 7.43(dd, J = 8.2, 2.4 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.43-5.31 (m, 1H),4.43-4.31 (m, 1H), 4.15-3.96 (m, 2H), 3.90- 3.65 (m, 4H), 3.46-3.32 (m,3H), 3.17-3.02 (m, 2H), 3.00-2.80 (m, 5H), 2.43 (s, 3H), 2.19 (s, 3H),2.09-1.77 (m, 6H), 1.71 (d, J = 6.6 Hz, 6H), 1.24 (d, J = 20.9 Hz, 6H).166 727 1H NMR (400 MHz, Methanol-d4) delta 8.25 (s, 0.1 1H), 8.11 (s,1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.74- 7.59 (m, 3H), 7.49 (d, J =7.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.45-4.35 (m, 1H), 4.11-3.79 (m,6H), 3.10-2.70 (m, 11H), 2.39 (s, 3H), 2.19 (s, 3H), 1.94- 1.80 (m, 6H),1.39-1.30 (m, 4H), 0.60-0.48 (m, 4H). 167 763.57 1H NMR (400 MHz,DMSO-d6) delta 9.45 (s, 1H), 0.1 8.50 (s, 1H), 8.26 (s, 1H), 8.20 (q, J= 4.5 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.86-7.78 (m, 3H), 7.65 (s,1H), 7.54 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.33 (s, 0H),4.16 (q, J = 5.4 Hz, 1H), 3.40 (d, J = 12.6 Hz, 5H), 2.98 (q, J = 9.9,9.4 Hz, 2H), 2.92- 2.79 (m, 2H), 2.77 (d, J = 4.5 Hz, 3H), 4.82-0.48 (m,1H), 2.32 (s, 3H), 2.00-1.80 (m, 8H), 1.75-1.54 (m, 5H), 1.49-1.33 (m,2H), 1.31-1.25 (m, 4H), 1.09-0.96 (m, 4H). 168 737.54 1H NMR (400 MHz,DMSO-d6) delta 9.41 (d, J = 0.1 9.4 Hz, 1H), 8.43 (s, 1H), 8.24 (s, 1H),8.20 (q, J = 4.6 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.86-7.83 (m, 1H),7.83-7.81 (m, 1H), 7.81 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.58 (d, J =7.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.33 (t, J = 8.0 Hz, 1H),4.19-4.10 (m, 1H), 3.60-3.34 (m, 6H), 3.00 (s, 3H), 2.92-2.78 (m, 2H),2.77 (d, J = 4.6 Hz, 3H), 2.32 (s, 3H), 2.00-1.79 (m, 5H), 1.67 (dd, J =36.8, 13.3 Hz, 3H), 1.41 (d, J = 12.8 Hz, 1H), 1.27 (dq, J = 5.6, 2.4Hz, 5H). 169 733.4 1H NMR (400 MHz, Methanol-d4) delta 9.37 (d, J = 0.131.6 Hz, 1H), 7.83 (d, J = 3.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H),7.64-7.60 (m, 3H), 7.51 (dd, J = 8.0, 3.9 Hz, 1H), 7.42 (s, 2H), 7.30(d, J = 8.2 Hz, 1H), 5.23 (s, 1H), 4.34 (t, J = 8.4 Hz, 1H), 3.87 (s,5H), 3.75 (d, J = 2.3 Hz, 3H), 3.68-3.45 (m, 4H), 3.07 (dq, J = 18.1,9.8, 9.3 Hz, 2H), 2.87 (t, J = 5.9 Hz, 8H), 2.45-2.41 (m, 4H), 2.15-1.64(m, 17H), 1.55 (q, J = 13.2 Hz, 2H), 0.98 (d, J = 9.2 Hz, 3H). 170 7531H NMR (400 MHz, Methanol-d4) delta 8.44 (s, 0.8 1H), 7.88 (d, J = 8.1Hz, 1H), 7.75 (s, 1H), 7.72- 7.65 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H),7.11 (d, J = 11.8 Hz, 1H), 5.26-5.18 (m, 1H), 4.79-4.64 (m, 5H),4.60-4.50 (m, 1H), 4.28-4.18 (m, 1H), 3.76- 3.68 (m, 2H), 2.88-2.56 (m,12H), 2.52-2.36 (m, 5H), 1.97-1.77 (m, 6H), 1.72-1.50 (m, 8H). 171 7671H NMR (400 MHz, Methanol-d4) delta 9.16 (s, 0.2 1H), 8.01-7.71 (m, 3H),7.58 (s, 1H), 7.51-7.34 (m, 1H), 7.16 (d, J = 11.5 Hz, 1H), 5.43-5.33(m, 1H), 5.10 (d, J = 44.5 Hz, 1H), 5.00-4.88 (m, 4H), 4.66- 4.52 m,1H), 4.38-4.25 (m, 1H), 3.81-3.33 (m, 10H), 3.19-2.85 (m, 5H), 2.46 (s,3H), 2.41-1.85 (m, 8H), 1.81-1.66 (m, 6H), 1.15 (t, J = 7.1 Hz, 3H). 172781 1H NMR (400 MHz, Methanol-d4) delta 8.90 (s, 0.3 1H), 7.95 (d, J =8.1 Hz, 1H), 7.82-7.76 (m, 2H), 7.62 (s, 1H), 7.44 (s, 1H), 7.14 (d, J =12.0 Hz, 1H), 5.31 (p, J = 6.3 Hz, 1H), 5.10 (d, J = 44.8 Hz, 1H),4.99-4.86 (m, 4H), 4.66-4.52 (m, 1H), 4.40-4.30 (m, 1H), 4.13 (p, J =6.5 Hz, 1H), 3.82-3.66 (m, 4H), 3.58-3.42 (m, 3H), 3.18-3.05 (m, 3H),3.00- 2.86 (m, 3H), 2.44 (s, 3H), 2.39-1.84 (m, 8H), 1.72 (d, J = 6.7,6H), 1.16 (d, J = 6.7, 6H). 173 715.5 1H NMR (400 MHz, DMSO-d6) delta10.74 (s, 1H), 0.08 9.50 (s, 1H), 8.36 (s, 1H), 8.26-7.46 (m, 7H), 7.20(d, J = 8.4 Hz, 1H), 4.78 (q, J = 7.6, 6.3 Hz, 4H), 4.59- 3.99 (m, 3H),3.43 (d, J = 9.1 Hz, 7H), 3.04-2.63 (m, 9H), 2.40-1.07 (m, 17H). 174678.5 1H NMR (400 MHz, DMSO-d6) delta 9.42 (d, J = 0.09 9.1 Hz, 1H),8.83 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 7.88 (s, 1H), 7.76 (d, J = 7.8Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 7.7 Hz,1H), 7.19 (d, J = 8.4 Hz, 1H), 5.40-5.28 (m, 1H), 4.55 (s, 1H), 4.43 (s,1H), 4.33-4.24 (m, 1H), 3.55-3.42 (m, 1H), 3.39 (d, J = 12.0 Hz, 2H),2.99-2.73 (m, 6H), 2.30 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.76-1.61(m, 2H), 1.57 (d, J = 6.4 Hz, 6H), 1.48-1.33 (m, 2H), 1.30 (s, 6H),0.90-0.84 (m, 2H), 0.83-0.77 (m, 2H). 175 638.4 1H NMR (400 MHz,DMSO-d6) delta 9.36 (d, J = 0.1 9.7 Hz, 1H), 8.77 (s, 1H), 8.41 (s, 1H),8.19 (q, J = 4.5 Hz, 1H), 7.84 (s, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H),7.61 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 7.8 Hz,1H), 7.25-7.14 (m, 1H), 5.28 (p, J = 6.6 Hz, 1H), 4.15 (p, J = 8.3 Hz,1H), 3.49 (p, J = 8.3 Hz, 1H), 3.37 (d, J = 11.8 Hz, 2H), 2.90 (dt, J =11.7, 8.9 Hz, 2H), 2.84-2.73 (m, 3H), 2.71 (d, J = 4.6 Hz, 3H), 2.36 (d,J = 0.6 Hz, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.76-1.60 (m, 2H), 1.58 (d,J = 6.6 Hz, 6H), 1.47-1.33 (m, 1H), 1.26 (s, 6H). 176 666.4 1H NMR (400MHz, DMSO-d6) delta 9.38 (d, J = 0.2 9.5 Hz, 1H), 8.74 (s, 1H), 8.43 (s,1H), 8.14 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.65 (dd, J = 7.8, 1.5 Hz,1H), 7.60 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 7.34 (d, J =7.8 Hz, 1H), 7.18 (d, J = 12.1 Hz, 1H), 5.29 (p, J = 6.6 Hz, 1H), 4.17(p, J = 8.3 Hz, 1H), 4.08-3.92 (m, 1H), 3.51 (h, J = 8.3 Hz, 1H), 3.38(d, J = 11.9 Hz, 2H), 2.99-2.85 (m, 2H), 2.85- 2.70 (m, 5H), 2.35 (d, J= 0.6 Hz, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.58 (d, J = 6.6 Hz, 9H), 1.38(q, J = 12.3 Hz, 1H), 1.26 (s, 6H), 1.07 (d, J = 6.6 Hz, 6H). 177 693.31H NMR (400 MHz, DMSO-d6) delta 9.38 (d, J = 0.4 9.7 Hz, 1H), 8.75 (s,1H), 8.43 (s, 1H), 8.20 (q, J = 4.5 Hz, 1H), 7.89 (s, 1H), 7.75 (dd, J =7.9, 1.4 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H),7.45 (d, J = 1.4 Hz, 1H), 7.19 (d, J = 12.1 Hz, 1H), 5.27 (q, J = 6.5Hz, 1H), 4.36-4.26 (m, 2H), 4.14 (q, J = 8.1 Hz, 2H), 4.08-3.95 (m, 2H),3.50 (q, J = 8.1 Hz, 1H), 3.37 (d, J = 11.6 Hz, 2H), 3.05-2.85 (m, 2H),2.83-2.69 (m, 6H), 2.39-2.31 (m, 3H), 1.84 (m, 5H), 1.70 (d, J = 13.0Hz, 1H), 1.58 (m, 7H), 1.40 (d, J = 13.0 Hz, 1H). 178 707.4 1H NMR (400MHz, DMSO-d6) delta 9.33 (s, 1H), 0.3 8.69 (s, 1H), 8.42 (s, 1H), 8.27(t, J = 5.6 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.64(d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H),7.18 (d, J = 12.1 Hz, 1H), 5.28 (p, J = 6.6 Hz, 1H), 4.30 (d, J = 9.2Hz, 2H), 4.16 (p, J = 8.3 Hz, 1H), 4.07-3.96 (m, 2H), 3.50 (q, J = 8.1Hz, 1H), 3.37 (d, J = 11.8 Hz, 2H), 3.27-3.14 (m, 2H), 2.94 (dt, J =27.9, 10.3 Hz, 2H), 2.85-2.68 (m, 4H), 2.36 (d, J = 0.6 Hz, 3H), 1.85(s, 5H), 1.57 (m, 8H), 1.41 (t, J = 12.6 Hz, 1H), 1.05 (t, J = 7.2 Hz,3H). 179 721.4 1H NMR (400 MHz, DMSO-d6) delta 9.32 (s, 1H), 1.1 8.67(s, 1H), 8.42 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.74 (dd,J = 7.8, 1.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.2 Hz,1H), 7.48 (d, J = 1.4 Hz, 1H), 7.17 (d, J = 12.4 Hz, 1H), 5.39-5.12 (m,1H), 4.31 (s, 2H), 4.17 (q, J = 8.2 Hz, 1H), 4.09- 3.95 (m, 3H), 3.50(q, J = 8.0 Hz, 1H), 3.38 (d, J = 11.5 Hz, 2H), 3.06-2.86 (m, 2H), 2.78(dd, J = 13.9, 8.4 Hz, 3H), 2.39-2.33 (m, 3H), 1.85 (s, 5H), 1.57 (d, J= 6.5 Hz, 8H), 1.39 (d, J = 12.6 Hz, 1H), 1.08 (d, J = 6.6 Hz, 6H). 180753 1H NMR (400 MHz, Methanol-d4) delta 8.46 (s, 0.2 1H), 8.08 (t, J =8.2 Hz, 1H), 7.77 (s, 1H), 7.72-7.66 (m, 1H), 7.63 (s, 1H), 7.43 (d, J =7.8 Hz, 1H), 7.21 (t, J = 10.4 Hz, 1H), 5.26-5.20 (m, 1H), 4.21-4.13 (m,2H), 4.07-3.97 (m, 2H), 3.97-3.88 (m, 1H), 3.84-3.76 (m, 1H), 2.79-2.36(m, 9H), 2.18 (s, 3H), 1.92-1.41 (m, 15H), 1.23 (d, J = 6.8, 6H). 181718 1H NMR (400 MHz, Methanol-d4) delta 9.18 (s, 0.2 1H), 7.97 (s, 1H),7.68 (dd, J = 7.9, 1.5 Hz, 1H), 7.50- 7.40 (m, 4H), 7.34 (dd, J = 8.3,2.5 Hz, 1H), 5.42- 5.30 (m, 1H), 4.33-4.217 (m, 1H), 4.10-3.97 (m, 2H),3.94-3.79 (m, 3H), 3.76-3.69 (m, 1H), 3.46- 3.36 (m, 2H), 3.14-2.96 (m,3H), 2.93-2.80 (m, 5H), 2.50 (s, 3H), 2.18 (s, 3H), 2.05-1.75 (m, 12H),1.25 (d, J = 24.0 Hz, 6H). 182 642 1H NMR (400 MHz, Methanol-d4) delta8.52 (s, 0.2 1H), 8.23 (d, J = 6.7 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J =7.5 Hz, 1H), 7.38 (dd, J = 7.5, 1.4 Hz, 1H), 7.18 (s, 1H), 6.12 (d, J =12.3 Hz, 1H), 5.73-5.63 (m, 1H), 4.64-4.46 (m, 1H), 2.93 (s, 3H), 2.48(m, 2H), 2.12 (m, 2H), 1.79 (t, J = 7.1 Hz, 6H), 1.47 (d, J = 20.6 Hz,6H), 1.35-1.11 (m, 8H), 0.92-0.83 (m, 2H).; 1H NMR (400 MHz, DMSO-d6)delta 8.50 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.93-7.76 (m, 3H), 7.60(d, J = 7.9 Hz, 1H), 7.46-7.37 (m, 1H), 7.28 (d, J = 7.8 Hz, 1H),5.27-5.17 (m, 1H), 4.37-7.27 (m, 1H), 3.28- 3.25 (m, 1H) 2.77 (d, J =3.6 Hz, 3H), 2.56-2.50 (m, 2H), 2.43-2.36 (m, 2H), 2.32-2.19 (m, 4H),1.60- 1.50 (m, 10H), 1.45-1.36 (m, 2H), 1.22 (s, 6H). 183 618.4 1H NMR(400 MHz, DMSO-d6) delta 9.06 (s, 1H), 0.05 8.32 (s, 1H), 8.20 (s, 1H),7.96 (d, J = 2.4 Hz, 1H), 7.89-7.82 (m, 2H), 7.80 (s, 1H), 7.71 (s, 1H),7.61 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H),4.46-4.37 (m, 1H), 3.29-3.17 (m, 2H), 3.02- 2.94 (m, 2H), 2.94-2.86 (m,2H), 2.77-2.70 (m, 3H), 2.34 (s, 3H), 1.87-1.79 (m, 3H), 1.74-1.63 (m,2H), 1.52 (s, 3H), 1.32 (s, 7H), 1.30-1.22 (m, 5H). 184 612.3 1H NMR(400 MHz, DMSO-d6) delta 9.29 (d, J = 0.9 10.4 Hz, 1H), 8.39 (s, 1H),8.27 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 8.07-8.00 (m, 1H), 7.94 (s, 1H),7.77 (q, J = 2.8, 2.3 Hz, 3H), 7.68 (dd, J = 8.2, 2.4 Hz, 1H), 7.43 (s,1H), 7.23 (d, J = 8.6 Hz, 1H), 4.43- 4.30 (m, 1H), 4.21-4.11 (m, 1H),3.40 (d, J = 11.9 Hz, 2H), 2.92 (t, J = 8.1 Hz, 4H), 2.87-2.73 (m, 2H),2.36 (s, 3H), 1.88-1.51 (m, 6H), 1.41 (t, J = 12.6 Hz, 1H), 1.31-1.23(m, 4H). 185 747.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.13 (bs, 1H), 8.97 0.1(s, 1H), 8.76-8.58 (m, 3H), 8.04 (s, 1H), 7.72 (s, 1H), 7.40 (d, J = 7.0Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.38-5.15 (m, 1H), 4.32 (m, 1H),3.23 (m, 2H), 2.93 (m, 4H), 2.70 (m, 2H), 2.28 (s, 3H), 1.85 (m, 2H),1.76-1.38 (m, 13H), 1.31 (s, 6H), 1.15-1.05 (m, 2H), 0.93 (m, 2H). 186729.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.09 (m, 1H), 8.80 .07 (s, 1H),8.73-8.60 (m, 3H), 8.03 (s, 1H), 7.72 (s, 1H), 7.37 (d, J = 6.9 Hz, 1H),5.32-5.17 (m, 1H), 4.49 (d, J = 52 Hz, 2H), 4.32 (m, 1H), 3.23 (m, 2H),2.94 (m, 4H), 2.76-2.59 (m, 2H), 2.28 (s, 3H), 1.85 (m, 2H), 1.69 (m,13H), 1.31 (m, 6H), 0.86 (m, 4H). 187 791.4 ¹H NMR (400 MHz, DMSO-d6) δ9.54 (bs, 1H), 8.97 0.2 (s, 2H), 8.70 (s, 1H), 8.66 (s, 1H), 8.03 (s,1H), 7.73 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H), 6.06 (t, J = 57.0 Hz, 1H),5.28 (m, 1H), 4.32 (m, 2H), 4.14 (m, 1H), 3.47 (m, 1H), 3.30 (m, 1H),3.15 (m, 2H), 2.90 (m, 1H), 2.72-2.05 (m, 8H), 1.62-1.52 (m, 9H), 1.30(s, 6H), 1.08 (m, 2H), 0.92-0.60 (m, 7H). 188 777.4 ¹H NMR (400 MHz,DMSO-d6) δ 9.19 (s, 1H), 8.98 0.4 (s, 1H), 8.71 (d, J = 8.0 Hz, 2H),8.03 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.1Hz, 1H), 5.38-5.20 (m, 1H), 4.41 (m, 1H), 3.87 (m, 2H), 3.28 (m, 3H),3.04 (m, 2H), 2.86 (m, 1H), 2.63 (m, 3H), 2.29 (s, 3H), 1.60 (m, 8H),1.45-1.19 (m, 12H), 1.07 (m, 2H), 0.93 (m, 2H). 189 775.4 ¹H NMR (400MHz, DMSO-d6) δ 10.09 (m, 1H), 0.2 8.98 (s, 1H), 8.71 (s, 2H), 8.68 (s,1H), 8.04 (s, 1H), 7.93 (d, J = 10.2 Hz, 1H), 7.43 (d, J = 6.9 Hz, 1H),6.07 (t, J = 57.0 Hz, 1H), 5.30 (m, 1H), 4.51 (m, 1H), 3.85-3.67 (m,4H), 3.58-3.43 (m, 3H), 3.33-3.10 (m, 3H), 3.02 (m, 2H), 2.82 (m, 2H),2.29 (s, 3H), 1.70-1.61 (m, 4H), 1.60 (m, 6H), 1.31 (s, 6H), 1.08 (m,2H), 0.93 (m, 2H). 190 775.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.54 (bs, 1H),8.98 0.07 (s, 1H), 8.69 (s, 2H), 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (s,1H), 7.41 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H),4.47-4.28 (m, 4H), 3.85 (m, 1H), 3.36 (m, 1H), 3.31 (m, 1H), 3.10 (m,1H), 3.01 (m, 1H), 2.79-2.59 (m, 2H), 2.34-2.23 (m, 4H), 2.03 (m, 1H),1.89-1.68 (m, 3H), 1.62 (m, 9H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m,2H). 191 775.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.54 (bs, 1H), 8.98 0.09 (s,1H), 8.69 (s, 2H), 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (d, J= 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.47-4.28 (m,4H), 3.85 (m, 1H), 3.36 (m, 1H), 3.31 (m, 1H), 3.10 (m, 1H), 3.01 (m,1H), 2.79-2.59 (m, 2H), 2.34-2.23 (m, 4H), 2.03 (m, 1H), 1.89-1.68 (m,3H), 1.62 (m, 9H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 192 775.4¹H NMR (400 MHz, DMSO-d6) δ 9.54 (bs, 1H), 8.98 0.1 (s, 1H), 8.69 (s,2H), 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (d, J = 7.0 Hz, 1H),6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.47-4.28 (m, 4H), 3.85 (m,1H), 3.36 (m, 1H), 3.31 (m, 1H), 3.10 (m, 1H), 3.01 (m, 1H), 2.79-2.59(m, 2H), 2.34-2.23 (m, 4H), 2.03 (m, 1H), 1.89-1.68 (m, 3H), 1.62 (m,9H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 193 775.4 ¹H NMR (400MHz, DMSO-d6) δ 9.78 (m, 1H), 8.96 0.2 (s, 1H), 8.69 (d, J = 8.8 Hz,2H), 8.64 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H),6.06 (t, J = 57.0 Hz, 1H), 5.27 (m, 1H), 4.36 (m, 1H), 4.00 (m, 1H),3.80 (m, 1H), 3.60 (m, 1H), 3.34 (m, 1H), 3.27- 3.12 (m, 2H), 3.01-2.89(m, 2H), 2.65 (m, 2H), 2.28 (s, 3H), 1.65-1.50 (m, 9H), 1.31 (s, 6H),1.11-1.04 (m, 2H), 0.96-0.86 (m, 3H), 0.84-0.70 (m, 3H). 194 773.5 ¹HNMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.97 0.06 (s, 1H), 8.69 (d, J =10.3 Hz, 2H), 8.64 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9Hz, 1H), 6.06 (t, J = 56.8 Hz, 1H), 5.27 (m, 1H), 4.30 (m, 1H), 3.33 (m,2H), 3.13 (m, 1H), 2.98 (m, 1H), 2.81 (m, 1H), 2.67 (s, 3H), 2.31 (m,2H), 2.08 (m, 1H), 1.90 (m, 3H), 1.65-1.47 (m, 7H), 1.31 (m, 7H), 1.08(m, 2H), 0.95 (m, 3H), 0.63 (m, 1H), 0.55-0.40 (m, 3H). 195 765.4 ¹H NMR(400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.92 0.07 (s, 1H), 8.75 (s, 1H), 8.68(s, 1H), 7.77 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.0 Hz,1H), 6.02 (t, J = 56.9 Hz, 1H), 5.29 (m, 1H), 4.24 (m, 1H), 3.19 (m,2H), 2.91 (s, 4H), 2.59 (m, 2H), 2.26 (s, 3H), 1.83- 1.36 (m, 15H), 1.31(s, 6H), 1.07 (m, 2H), 0.89 (m, 2H). 196 765.4 ¹H NMR (400 MHz, DMSO-d6)δ 9.46 (m, 1H), 8.97 0.1 (s, 1H), 8.70 (d, J = 5.8 Hz, 2H), 8.65 (s,1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.07 (t, J =57.0 Hz, 1H), 5.34-5.26 (m, 1H), 5.19 (m, 1H), 4.33 (m, 1H), 3.59-3.43(m, 1H), 3.43-3.18 (m, 2H), 3.15-2.86 (m, 3H), 2.76-2.60 (m, 2H), 2.29(s, 3H), 2.05 (m, 14H), 1.31 (s, 6H), 1.12-1.02 (m, 2H), 0.93 (m, 2H).197 765 ¹H NMR (400 MHz, DMSO-d6) δ 9.54 (m, 1H), 8.97 0.1 (s, 1H),8.81-8.49 (m, 3H), 8.04 (s, 1H), 7.75 (s, 1H), 7.41 (m, 1H), 6.07 (t, J= 57.0 Hz, 1H), 5.39- 5.14 (m, 1H), 5.02 (m, 1H), 4.33 (m, 1H),3.40-2.98 (m, 7H), 2.71 (m, 2H), 2.38-1.84 (m, 7H), 1.65- 1.43 (m, 9H),1.30 (s, 6H), 1.00 (m, 4H). 198 783.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.61(bs, 1H), 9.17 0.01 (s, 1H), 8.94 (s, 1H), 8.80-8.62 (m, 2H), 8.10 (s,1H), 7.70 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 7.5, 2.2 Hz, 1H), 6.04 (t,J = 56.7 Hz, 1H), 5.26 (m, 1H), 4.29 (m, 1H), 3.93-3.76 (m, 3H),3.39-3.19 (m, 4H), 2.99 (m, 2H), 2.72 (m, 2H), 2.05 (m, 2H), 1.71-1.49(m, 10H), 1.31 (s, 6H), 1.21-1.03 (m, 2H), 1.03- 0.88 (m, 2H). 199 769.3¹H NMR (400 MHz, DMSO-d6) δ 9.93 (bs, 1H), 9.17 0.1 (s, 1H), 8.95 (s,1H), 8.72 (d, J = 1.7 Hz, 1H), 8.69 (s, 1H), 8.11 (s, 1H), 7.76 (d, J =1.8 Hz, 1H), 7.51 (m, 1H), 6.05 (t, J = 57.0 Hz, 1H), 5.26 (m, 1H), 4.38(m, 1H), 4.03 (m, 2H), 3.70 (m, 2H), 3.27 (m, 2H), 3.18- 3.00 (m, 4H),2.64 (m, 2H), 1.62-1.54 (m, 9H), 1.31 (s, 6H), 1.12-1.08 (m, 2H),0.96-0.91 (m, 2H). 200 771.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H),8.94 0.1 (s, 1H), 8.71 (s, 1H), 8.69 (m, 2H), 8.11 (s, 1H), 7.97 (m,1H), 7.54 (dd, J = 7.5, 2.1 Hz, 1H), 6.05 (t, J = 56.7 Hz, 1H), 5.52 (m,1H), 5.27 (m, 1H), 4.58 (m, 1H), 3.97-3.68 (m, 2H), 3.67-3.38 (m, 2H),3.28- 3.15 (m, 2H), 2.47-2.34 (m, 3H), 2.34-1.95 (m, 1H), 1.66 (m, 3H),1.59 (s, 6H), 1.31 (s, 6H), 1.12- 1.07 (m, 2H), 0.96-0.90 (m, 2H). 201785.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.49 (m, 1H), 9.18 0.2 (s, 1H), 8.96(s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.70 (d,J = 1.8 Hz, 1H), 7.50 (dd, J = 7.5, 2.0 Hz, 1H), 6.05 (t, J = 56.8 Hz,1H), 5.32- 5.11 (m, 2H), 4.33 (m, 1H), 3.57-3.17 (m, 3H), 3.15- 2.94 (m,3H), 2.74-2.57 (m, 2H), 2.05-1.64 (m, 4H), 1.59 (d, J = 6.5 Hz, 6H),1.54 (s, 3H), 1.32 (s, 6H), 1.12-1.08 (m, 2H), 0.96-0.91 (m, 2H). 202749.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.05 (m, 2H), 8.75 0.1 (s, 1H), 8.63(d, J = 13.0 Hz, 2H), 8.07 (s, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.2 Hz,1H), 7.57 (d, J = 10.8 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.36-5.16 (m,1H), 4.44-4.17 (m, 1H), 3.23 (m, 2H), 2.94 (m, 4H), 2.67 (m, 2H), 1.86(m, 2H), 1.67-1.24 (m, 19H), 1.08 (m, 2H), 0.92 (m, 2H). 203 793.3 ¹HNMR (400 MHz, DMSO-d6) δ 9.14 (m, 2H), 8.95 0.07 (s, 1H), 8.76-8.62 (m,2H), 8.09 (s, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.51 (m, 1H), 6.04 (t, J =56.7 Hz, 1H), 5.26 (m, 1H), 4.30 (m, 1H), 3.41-3.23 (m, 2H), 3.14 (t, J= 10.4 Hz, 1H), 3.00 (m, 1H), 2.84 (t, J = 10.4 Hz, 1H), 2.64 (m, 2H),2.00-1.77 (m, 3H), 1.59- 1.52 (m, 10H), 1.31 (s, 6H), 1.17-1.03 (m, 2H),0.95 (m, 3H), 0.65-0.57 (m, 1H), 0.49 (m, 3H). 204 785.3 ¹H NMR (400MHz, DMSO-d6) δ 9.40 (s, 1H), 9.20 0.2 (d, J = 10.3 Hz, 1H), 8.96 (s,1H), 8.78-8.44 (m, 2H), 8.11 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.49 (m,1H), 5.26 (m, 1H), 4.32 (m, 1H), 3.23 (m, 2H), 3.01- 2.74 (m, 4H), 2.67(m, 2H), 1.97-1.20 (m, 23H), 1.14 (m, 2H). 205 779.3 ¹H NMR (400 MHz,DMSO-d6) δ 10.15 (m, 1H), 0.1 9.17 (s, 1H), 8.92 (s, 1H), 8.70 (s, 1H),8.66 (s, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.97 (s, 1H), 7.59-7.49 (m, 1H),6.05 (t, J = 56.3 Hz, 1H), 5.26 (m, 1H), 4.63- 4.52 (m, 1H), 3.72 (m,2H), 3.33 (m, 4H), 3.07 (m, 2H), 2.22 (m, 2H), 1.88-1.24 (m, 18H), 1.10(m, 2H), 0.94 (m, 2H). 206 771.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.17 (bs,1H), 8.86 0.07 (s, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.03(s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.19 (d, J = 12.0 Hz, 1H), 6.09 (t,J = 57.2 Hz, 1H), 5.29 (m, 1H), 4.33 (m, 1H), 4.11 (m, 1H), 3.98-3.88(m, 1H), 3.22 (m, 2H), 3.02-2.84 (m, 4H), 2.70-2.61 (m, 2H), 2.35 (m,3H), 1.85-1.35 (m, 21H), 1.07 (m, 2H), 0.92 (m, 2H). 207 767.3 ¹H NMR(400 MHz, DMSO-d6) δ 9.14 (m, 2H), 8.89 0.08 (s, 1H), 8.63 (m, 2H), 8.04(s, 1H), 7.64 (s, 1H), 7.43 (m, 1H), 5.98 (t, J = 56.8 Hz, 1H), 5.20 (m,1H), 4.25 (m, 1H), 3.16 (m, 2H), 2.96-2.77 (m, 4H), 2.62 (m, 2H),1.78-1.45 (m, 15H), 1.24 (s, 6H), 1.04 (m, 2H), 0.87 (m, 2H). 208 763.4¹H NMR (400 MHz, DMSO-d6) δ 9.61 (bs, 1H), 8.97 0.09 (s, 1H), 8.69-8.63(m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 7.0 Hz,1H), 6.07 (t, J = 56.4 Hz, 1H), 5.35-5.21 (m, 1H), 4.40-4.22 (m, 1H),3.30 (m, 8H), 2.99 (m, 2H), 2.74 (m, 5H), 2.31 (m, 3H), 2.16-1.94 (m,2H), 1.66-1.50 (m, 8H), 1.31 (m, 4H), 1.08 (m, 2H), 0.93 (m, 2H). 209759.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.25 (bs, 1H), 0.08 8.98 (s, 1H),8.74-8.64 (m, 3H), 8.05 (s, 1H), 7.97 (s, 1H), 7.44 (d, J = 6.8 Hz, 1H),6.07 (t, J = 57.1 Hz, 1H), 5.29 (m, 1H), 4.57 (m, 1H), 3.77-3.49 (m,2H), 3.32 (m, 4H), 3.21-2.93 (m, 2H), 2.43 (m, 2H), 2.29 (m, 5H), 1.95(m, 11H), 1.30 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 210 809.3 ¹H NMR(400 MHz, DMSO-d6) δ 9.14 (m, 2H), 8.94 0.08 (s, 1H), 8.77 (d, J = 1.7Hz, 1H), 8.65 (s, 1H), 8.13 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.51 (dd,J = 7.5, 2.1 Hz, 1H), 6.04 (t, J = 56.8 Hz, 1H), 5.25 (m, 1H), 4.32 (m,1H), 4.11 (m, 2H), 3.94 (m, 2H), 3.22 (m, 2H), 3.08-2.84 (m, 4H),2.71-2.59 (m, 2H), 1.84-1.43 (m, 20H), 1.18-1.03 (m, 2H), 0.93 (m, 2H).211 749 ¹H NMR (400 MHz, DMSO-d6) δ 9.15 (bs, 1H), 9.01 0.1 (s, 1H),8.92 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.71(d, J = 1.8 Hz, 1H), 7.47 (m, 1H), 5.26 (m, 1H), 4.47 (d, J = 49.0 Hz,2H), 4.32 (m, 1H), 3.23 (m, 2H), 2.95 (m, 4H), 2.67 (m, 2H), 1.85 (m,2H), 1.81-1.38 (m, 13H), 1.31 (s, 6H), 0.95- 0.75 (m, 4H). 212 757.4 ¹HNMR (400 MHz, DMSO-d6) δ 9.79 (bs, 1H), 8.87 0.3 (s, 1H), 8.77 (s, 1H),8.69 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.21 (d, J = 12.0 Hz, 1H), 6.10 (t, J = 57.3 Hz, 1H), 5.38-5.26 (m, 1H), 4.70-4.57 (m, 1H), 4.49-4.43 (m, 2H), 3.96 (m, 2H), 3.82(m, 2H), 3.52-3.37 (m, 1H), 2.46-2.33 (m, 5H), 2.15 (m, 2H), 2.10-1.99(m, 2H), 1.69 (s, 3H), 1.61 (d, J = 6.4 Hz, 6H), 1.31 (s, 6H), 1.09-1.04(m, 2H), 0.95-0.90 (m, 2H). 213 743.4 ¹H NMR (400 MHz, DMSO-d6) δ 8.98(m, 1H), 8.86 0.3 (s, 1H), 8.73 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H),8.01 (s, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 12.1Hz, 1H), 6.10 (t, J = 57.3 Hz, 1H), 5.29 (m, 1H), 4.21 (m, 1H), 3.28 (m,2H), 2.96 (m, 3H), 2.87 (m, 3H), 2.35 (s, 3H), 1.91-1.80 (m, 4H), 1.69(m, 3H), 1.59 (d, J = 6.4 Hz, 6H), 1.50-1.39 (m, 1H), 1.31 (s, 6H), 1.16(m, 3H), 1.07 (m, 2H), 0.92 (m, 2H). 214 733.4 ¹H NMR (400 MHz, DMSO-d6)δ 9.23 (bs, 1H), 8.97 0.1 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 8.24 (s,1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 6.08 (t, J =57.0 Hz, 1H), 5.27 (m, 1H), 4.06 (m, 1H), 3.34- 3.13 (m, 4H), 2.92 (m,2H), 2.37-2.27 (m, 5H), 1.88 (m, 2H), 1.80-1.65 (m, 3H), 1.58-1.50 (m,9H), 1.48-1.39 (m, 2H), 1.31 (s, 6H), 1.28 (m, 1H), 1.07 (m, 2H), 0.92(m, 2H). 215 731.4 ¹H NMR (400 MHz, DMSO-d6) δ 10.12 (bs, 1H), 0.1 8.87(s, 1H), 8.82 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.00 (d, J = 1.4 Hz,1H), 7.78 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 11.9 Hz, 1H),6.10 (t, J = 57.4 Hz, 1H), 5.39-5.27 (m, 1H), 4.44-4.31 (m, 1H), 4.02(m, 2H), 3.71 (m, 2H), 3.28-3.23 (m, 1H), 3.16- 3.00 (m, 5H), 2.69-2.59(m, 2H), 2.36 (s, 3H), 1.64- 1.54 (m, 9H), 1.30 (s, 6H), 1.10-1.05 (m,2H), 0.95- 0.90 (m, 2H). 216 729.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.12 (bs,1H), 8.85 0.1 (s, 1H), 8.73 (s, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.45 (s,1H), 8.00 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.65- 7.58 (m, 1H), 7.19(d, J = 11.6 Hz, 1H), 6.09 (t, J = 57.8 Hz, 1H), 5.34-5.25 (m, 1H),4.36-4.27 (m, 1H), 3.23 (m, 2H), 3.00-2.87 (m, 4H), 2.73-2.62 (m, 2H),2.35 (s, 3H), 1.85 (m, 2H), 1.75-1.63 (m, 3H), 1.62-1.04 (m, 16H),1.09-1.04 (m, 2H), 0.94- 0.89 (m, 2H). 217 721.3 ¹H NMR (400 MHz,DMSO-d6) δ 9.13 (m, 1H), 8.80 0.06 (d, J = 6.7 Hz, 1H), 8.76-8.64 (m,3H), 8.03 (d, J = 2.3 Hz, 1H), 7.70 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H),6.39-5.29 (m, 2H), 4.31 (m, 1H), 3.23 (m, 2H), 2.93 (m, 4H), 2.69 (m,2H), 2.31 (s, 3H), 1.84 (m, 2H), 1.69 (m, 3H), 1.59 (m, 6H), 1.51 (s,3H), 1.44 (m, 1H), 1.30 (m, 5H). 218 715.4 ¹H NMR (400 MHz, DMSO-d6) δ9.16-9.11 (m, 0.06 1H), 9.02 (s, 1H), 8.74 (s, 2H), 8.63 (s, 1H), 8.11-8.01 (m, 2H), 7.77-7.63 (m, 3H), 7.49 (m, 1H), 7.44- 7.34 (m, 1H), 6.10(t, J = 57.5 Hz, 1H), 5.37-5.26 (m, 1H), 4.32-4.21 (m, 1H), 3.18 (m,2H), 2.96- 2.84 (m, 4H), 2.58 (m, 2H), 1.85 (m, 2H), 1.73-1.62 (m, 3H),1.60 (m, 6H), 1.50 (s, 3H), 1.45-1.37 (m, 1H), 1.29 (s, 6H), 1.12-1.07(m, 2H), 0.95-0.90 (m, 2H). 219 715.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.22(bs, 1H), 8.85 0.2 (s, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H),7.91 (s, 1H), 7.67-7.53 (m, 2H), 7.46 (s, 1H), 7.17 (d, J = 12.1 Hz,1H), 6.11 (t, J = 57.3 Hz, 1H), 5.32-5.22 (m, 1H), 4.10-4.03 (m, 1H),3.34-3.14 (m, 4H), 2.92 (m, 2H), 2.37-2.27 (m, 5H), 1.88 (m, 2H), 1.80-1.65 (m, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.50 (s, 3H), 1.48-1.39 (m, 2H),1.31 (s, 6H), 1.28 (m, 1H), 1.07 (m, 2H), 0.92 (m, 2H). 220 699.4 ¹H NMR(400 MHz, DMSO-d6) δ 9.16-9.03 (m, 0.09 1H), 8.76-8.56 (m, 3H), 8.27 (d,J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 7.35 (d, J = 6.9 Hz, 1H),5.27 (m, 1H), 4.31 (m, 1H), 4.03 (m, 1H), 3.24 (m, 2H), 2.93 (m, 5H),2.83-2.65 (m, 2H), 2.29 (s, 3H), 1.85 (d, J = 13.6 Hz, 2H), 1.69 (m,3H), 1.64-1.30 (m, 15H), 1.12 (m, 6H). 221 697.4 ¹H NMR (400 MHz,DMSO-d6) δ 9.12 (s, 1H), 8.75- 0.07 8.59 (m, 2H), 8.44 (d, J = 4.1 Hz,1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.34 (d, J = 6.9 Hz, 1H), 5.39-5.15 (m,1H), 4.46-4.20 (m, 1H), 3.23 (m, 2H), 2.93 (m, 4H), 2.82 (m, 1H), 2.69(m, 2H), 2.29 (m, 2H), 1.85 (m, 2H), 1.69 (m, 3H), 1.62-1.40 (m, 9H),1.31 (m, 5H), 0.67 (m, 2H), 0.58-0.43 (m, 2H). 222 685.4 ¹H NMR (400MHz, DMSO-d6) δ 9.21 (s, 1H), 8.71 0.06 (d, J = 3.5 Hz, 3H), 8.40 (d, J= 6.3 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.70 (s, 1H), 7.36 (d, J = 7.0Hz, 1H), 5.30 (m, 1H), 3.31-3.10 (m, 4H), 2.93 (m, 4H), 2.69 (m, 2H),2.30 (s, 3H), 1.84 (m, 2H), 1.70 (m, 3H), 1.64-1.58 (m, 5H), 1.52 (m,2H), 1.42 (m, 1H), 1.30 (m, 5H), 1.08 (m, 3H). 223 653.4 ¹H NMR (400MHz, DMSO-d6) δ 9.30 (m, 1H), 0.2 8.78 (dd, J = 12.6, 2.4 Hz, 2H), 8.65(s, 1H), 8.52 (d, J = 6.5 Hz, 1H), 8.11-8.01 (m, 2H), 7.70-7.64 (m, 2H),7.44-7.34 (m, 1H), 5.40-5.28 (m, 1H), 4.32- 4.19 (m, 1H), 3.35-3.22 (m,1H), 3.16 (m, 2H), 2.96- 2.83 (m, 4H), 2.60-2.51 (m, 2H), 1.84 (m, 2H),1.71-1.42 (m, 14H), 1.29 (s, 6H), 1.11 (m, 3H). 224 775.4 ¹H NMR (400MHz, DMSO-d6) δ 10.23 (bs, 1H), 0.06 9.93 (s, 1H), 8.98 (s, 1H), 8.67(m, 3H), 8.04 (d, J = 12.1 Hz, 2H), 7.44 (d, J = 6.9 Hz, 1H), 6.07 (t, J= 57.0 Hz, 1H), 5.29 (m, 1H), 4.67 (m, 1H), 4.39-4.26 (m, 1H), 4.04 (m,4H), 3.80 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.54-3.40 (m, 1H), 3.26(m, 1H), 2.53 (m, 2H), 2.45 (m, 1H), 2.17-1.24 (m, 18H), 1.08 (m, 2H),0.93 (m, 2H). 225 779.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.17-9.11 (m, 0.082H), 8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J =2.7 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.04 (t, J = 56.6Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.02 (m, 2H), 2.88(m, 2H), 2.65 (m, 3H), 2.25 (s, 1H), 1.98 (m, 1H), 1.64-1.51 (m, 6H),1.44-1.10 (m, 11H), 0.93 (m, 2H), 0.78 (m, 1H), 0.62 (m, 1H). 226 781.3¹H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.78- 0.1 8.59 (m, 3H), 8.50(s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J = 7.0 Hz,1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.42 (m, 1H), 3.23 (m,4H), 3.10 (m, 2H), 2.43 (m, 2H), 2.29 (s, 3H), 1.79-1.55 (m, 14H),1.52-1.40 (m, 1H), 1.32 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 227 761.3¹H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 9.01 0.1 (s, 1H), 8.92 (s,1H), 8.73 (d, J = 1.8 Hz, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 7.68 (d, J =1.8 Hz, 1H), 7.47 (dd, J = 7.5, 2.0 Hz, 1H), 5.26 (m, 1H), 4.48 (d, J =52 Hz, 2H), 4.30 (m, 1H), 3.63 (m, 1H), 3.10-2.95 (m, 2H), 2.95-2.79 (m,2H), 2.73-2.57 (m, 2H), 2.35- 2.16 (m, 1H), 2.04-1.90 (m, 1H), 1.66-1.50(m, 6H), 1.44 (s, 3H), 1.34-1.29 (m, 6H), 1.22 (m, 1H), 1.15-1.04 (m,1H), 0.91 (m, 2H), 0.88-0.70 (m, 3H), 0.63 (m, 1H). 228 775.4 ¹H NMR(400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.97 0.3 (s, 1H), 8.69 (d, J = 10.5Hz, 2H), 8.63 (s, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.42 (d, J = 7.0 Hz,1H), 6.07 (t, J = 56.9 Hz, 1H), 5.38-5.15 (m, 1H), 4.57 (s, 2H), 4.49(m, 1H), 3.32 (m, 2H), 3.27-3.10 (m, 4H), 2.29 (s, 3H), 2.02 (m, 4H),1.62 (m, 11H), 1.32 (s, 6H), 1.07 (m, 2H), 0.93 (m, 2H). 229 761.4 ¹HNMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.97 0.08 (s, 1H), 8.71 (s, 1H),8.68 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71(s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.36-5.13(m, 1H), 4.28 (m, 1H), 3.23 (m, 2H), 3.11 (m, 2H), 2.95 (m. 2H),2.81-2.70 (m, 2H), 2.28 (m, 2H), 1.89 (m, 2H), 1.77 (m, 2H), 1.64 (m,4H), 1.61-1.55 (m, 6H), 1.53 (m, 2H), 1.31 (s, 6H), 1.08 (m, 2H), 0.92(m, 2H). 230 773.4 ¹H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.78- 0.18.59 (m, 3H), 8.50 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.42(d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.42 (m,1H), 3.23 (m, 4H), 3.10 (m, 2H), 2.43 (s, 3H), 2.29 (s, 3H), 1.79 (s,4H), 1.70 (m, 1H), 1.65-1.55 (m, 9H), 1.52-1.40 (m, 1H), 1.32 (s, 6H),1.08 (m, 2H), 0.93 (m, 2H). 231 759.4 ¹H NMR (400 MHz, DMSO-d6) δ9.24-9.08 (m, 0.1 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz,1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H),5.36-5.22 (m, 1H), 4.37-4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88(m, 2H), 2.67 (m, 3H), 2.29 (s, 4H), 1.97 (m, 1H), 1.59 (d, J = 6.3 Hz,6H), 1.44 (s, 3H), 1.31-1.24 (m, 7H), 1.09 (m, 3H), 0.93 (m, 3H), 0.78(m, 1H), 0.61 (m, 1H). 232 759.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.24-9.08(m, 0.09 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.70(s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.36-5.22(m, 1H), 4.37-4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H),2.67 (m, 3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (d, J = 6.3 Hz, 6H), 1.44(s, 3H), 1.31-1.24 (m, 7H), 1.09 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H),0.61 (m, 1H). 233 759.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.24-9.08 (m, 0.081H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H),7.41 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.36-5.22 (m, 1H),4.37-4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.67 (m,3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (d, J = 6.3 Hz, 6H), 1.44 (s, 3H),1.31-1.24 (m, 7H), 1.09 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.61 (m,1H). 234 765.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.17 0.3 (s,1H), 8.91 (s, 1H), 8.69 (d, J = 1.7 Hz, 1H), 8.65 (s, 1H), 8.11 (s, 1H),7.98 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 7.5, 2.1 Hz, 1H), 6.05 (t, J =56.8 Hz, 1H), 5.26 (m, 1H), 4.56 (m, 1H), 3.57 (m, 4H), 3.25 (m, 2H),2.43- 2.35 (m, 2H), 1.84 (m, 2H), 1.65 (s, 3H), 1.59 (m, 7H), 1.31 (s,6H), 1.13-1.05 (m, 2H), 0.97-0.87 (m, 2H), 0.76 (m, 1H), 0.65 (m, 1H).235 728.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.17 (m, 1H), 8.84 0.1 (d, J = 2.1Hz, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.71-7.60(m, 2H), 7.45 (s, 1H), 7.36 (dd, J = 7.9, 2.3 Hz, 1H), 7.16 (dd, J =12.1, 2.3 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.30 (m, 1H), 4.38-4.19(m, 1H), 3.22 (m, 2H), 2.94 (m, 4H), 2.64 (m, 2H), 2.34 (d, J = 2.2 Hz,3H), 1.84 (m, 2H), 1.78- 1.64 (m, 3H), 1.59 (m, 6H), 1.51 (s, 3H), 1.29(s, 6H), 1.07 (m, 2H), 0.87 (m, 2H). 236 746.4 ¹H NMR (400 MHz, DMSO-d6)δ 9.13 (s, 1H), 8.95 0.07 (d, J = 2.6 Hz, 1H), 8.67 (s, 2H), 7.93 (d, J= 2.6 Hz, 1H), 7.60 (m, 2H), 7.46-7.34 (m, 4H), 6.07 (t, J = 57.0 Hz,1H), 5.28 (m, 1H), 4.30 (m, 1H), 3.22 (d, J = 11.8 Hz, 3H), 2.93 (m,5H), 2.68 (d, J = 8.6 Hz, 3H), 2.27 (s, 3H), 1.84 (d, J = 13.3 Hz, 3H),1.78- 1.36 (m, 14H), 1.29 (m, 7H), 1.07 (m, 3H), 0.89 (m, 3H). 237 732.4¹H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.95 0.3 (s, 1H), 8.66 (d, J =26.4 Hz, 2H), 7.76 (s, 1H), 7.39 (d, J = 6.9 Hz, 1H), 7.21 (d, J = 7.7Hz, 1H), 7.02 (d, J = 4.1 Hz, 2H), 6.06 (t, J = 57.0 Hz, 1H), 5.37-5.19(m, 1H), 3.90 (m, 1H), 3.23-3.06 (m, 4H), 3.00- 2.79 (m, 3H), 2.27 (d, J= 9.2 Hz, 6H), 1.94-1.35 (m, 17H), 1.26 (s, 6H), 1.08 (m, 2H), 0.89 (m,3H). 238 714.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.04 (bs, 1H), 8.99 0.02 (s,1H), 8.64 (d, J = 2.6 Hz, 1H), 8.54 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H),7.94 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.62 (m, 1H), 7.43(s, 1H), 7.35 (m, 2H), 6.08 (t, J = 57.3 Hz, 1H), 5.28 (m, 1H), 4.21 (m,1H), 3.17 (m, 3H), 2.89 (m, 5H), 1.85 (m, 3H), 1.80- 1.63 (m, 2H),1.63-1.55 (m, 6H), 1.47 (m, 4H), 1.28 (s, 6H), 1.10 (m, 2H), 0.91 (m,2H). 239 684.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.06 (m, 1H), 8.61 0.04 (s,2H), 8.37 (m, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H),7.48-7.33 (m, 3H), 5.26 (m, 1H), 4.30 (m, 1H), 3.30-3.15 (m, 4H),3.05-2.84 (m, 4H), 2.68 (m, 2H), 2.29 (s, 3H), 1.84 (m, 2H), 1.69-1.42(m, 13H), 1.29 (s, 6H), 1.06 (m, 3H). 240 652.4 ¹H NMR (400 MHz,DMSO-d6) δ 9.12 (bs, 1H), 8.71 0.09 (s, 1H), 8.55 (s, 1H), 8.49 (d, J =5.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.70(d, J = 7.9 Hz, 1H), 7.61 (m, 1H), 7.42 (s, 1H), 7.36 (m, 3H), 5.31 (m,1H), 4.21 (m, 1H), 3.28 (m, 3H), 3.15 (m, 2H), 2.97-2.80 (m, 5H), 1.84(m, 2H), 1.78- 1.63 (m, 2H), 1.62-1.54 (m, 5H), 1.47 (m, 4H), 1.28 (s,6H), 1.10 (m, 4H). 241 766.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.12 (m, 2H),8.69 0.1 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.50 (d, J =7.5, 2.0 Hz, 1H), 7.43-7.38 (m, 3), 6.02 (t, J = 56.8 Hz, 1H), 5.25 (m,1H), 4.30 (m, 1H), 3.23 (m, 2H), 2.98 (m, 4H), 2.63 (m, 2H), 1.85 (m,2H), 1.69- 1.51 (m, 13H), 1.30 (s,6H), 1.10 (m, J = 6.3 Hz, 2H), 0.90(m, 2H). 242 733.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.20 (m, 1H), 0.07 9.08(s, 1H), 8.91 (s, 1H), 8.73 (d, J = 5.8 Hz, 2H), 8.09 (d, J = 2.0 Hz,1H), 7.90 (d, J = 6.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 6.08 (t, J =57.1 Hz, 1H), 5.31 (m, 2H), 4.28 (m, 1H), 3.19 (m, 2H), 2.93 (m, 4H),2.62 (m, 2H), 2.53-2.44 (m, 2H), 1.85-1.19 (m, 18H), 1.11 (m, 2H), 0.94(m, 2H). 243 732.4 ¹H NMR (400 MHz, Methanol-d4) δ 9.22-9.06 (m, 0.052H), 8.06 (d, J = 6.2 Hz, 1H), 7.93 (s, 1H), 7.77- 7.46 (m, 3H), 7.40(dd, J = 7.8, 2.4 Hz, 1H), 5.96 (t, J = 57.3 Hz, 1H), 5.41 (m, 1H),4.49-4.35 (m, 1H), 3.38 (m, 3H), 3.04 (m, 5H), 2.74 (m, 2H), 2.06 (m,3H), 1.94-1.69 (m, 10H), 1.66-1.49 (m, 4H), 1.49- 1.35 (m, 9H), 1.18 (m,2H), 0.98 (m, 3H). 244 752.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.46-9.26 (m,0.05 1H), 9.15 (s, 1H), 8.95-8.86 (m, 1H), 8.73-8.61 (m, 1H), 7.97 (s,1H), 7.65 (m, 1H), 7.52 (m, 1H), 7.46 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H),6.02 (t, J = 56.7 Hz, 1H), 5.25 (m, 1H), 4.20 (m, 1H), 3.54-3.34 (m,3H), 3.04-2.92 (m, 2H), 2.89-2.72 (m, 4H), 1.85 (m, 2H), 1.78-1.53 (m,9H), 1.49-1.36 (m, 1H), 1.29 (s, 6H), 1.13-1.06 (m, 2H), 0.95-0.86 (m,2H). 245 753.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.17 0.1 (s,1H), 8.93 (s, 1H), 8.72 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 1.2 Hz, 1H),8.08 (s, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.54 (m, 1H), 6.04 (t, J = 56.7Hz, 1H), 5.26 (m, 1H), 4.32-4.15 (m, 1H), 3.49 (m, 1H), 3.41 (m, 2H),3.00-2.89 (m, 2H), 2.89-2.76 (m, 4H), 1.85 (m, 2H), 1.76-1.54 (m, 9H),1.50-1.36 (m, 1H), 1.30 (s, 6H), 1.14-1.06 (m, 2H), 0.97-0.87 (m, 2H).246 733.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J = 9.2 0.04 Hz, 1H),8.98 (s, 1H), 8.70 (m, 3H), 8.01 (d, J = 1.6 Hz, 1H), 7.76 (s, 1H), 7.43(d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.30 (m, 1H), 4.40-4.05(m, 1H), 3.45 (m, 3H), 2.88 (m, 6H), 2.30 (m, 3H), 2.00- 1.52 (m, 12H),1.30 (m, 7H), 1.12-0.85 (m, 4H). 247 719.3 ¹H NMR (400 MHz, DMSO-d6) δ8.87 (s, 1H), 8.61 0.05 (m, 2H), 8.56 (m, 1H), 8.15 (d, J = 1.8 Hz, 1H),7.94 (s, 1H), 7.53-7.42 (m, 1H), 5.26 (m, 1H), 4.65 (m, 1H), 3.24 (m,2H), 2.62 (m, 2H), 2.45 (m, 4H), 2.20 (m, 2H), 1.58 (m, 14H), 1.28 (s,6H), 1.18 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). 248 755.3 ¹H NMR (400 MHz,DMSO-d6) δ 9.01 (m, 1H), 8.92 0.05 (s, 1H), 8.66-8.55 (m, 2H), 8.14 (d,J = 1.8 Hz, 1H), 7.95 (s, 1H), 7.53 (m, 1H), 6.13 (tt, J = 55.6, 3.8 Hz,1H), 5.25 (m, 1H), 4.65 (m, 1H), 3.67 (m, 2H), 2.62 (m, 2H), 2.45 (m,3H), 2.20 (m, 2H), 2.07 (s, 1H), 1.58 (m, 14H), 1.28 (s, 6H), 1.18 (s,3H). 249 763.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 9.01 0.04 (s,1H), 8.90 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.65 (s, 1H), 8.10 (s, 1H),7.70 (d, J = 1.8 Hz, 1H), 7.47 (m, 1H), 5.25 (m, 1H), 4.47 (d, J = 49.0Hz, 2H), 4.28 (m, 1H), 3.21 (m, 2H), 3.11 (m, 2H), 2.96 (m, 2H), 2.77-2.68 (m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.64 (m, 4H), 1.58 (d, J = 6.6Hz, 6H), 1.54 (s, 3H), 1.31 (s, 6H), 0.91 (m, 2H), 0.85 (m, 2H). 250741.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.19 (s, 1H), 0.1 9.02 (m, 2H),8.85-8.58 (m, 2H), 8.11 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.49 (m, 1H),6.39-5.91 (m, 1H), 5.27 (m, 1H), 4.31 (m, 1H), 3.67 (m, 2H), 3.23 (m,2H), 3.03-2.80 (m, 4H), 2.67 (m, 2H), 1.78 (m, 4H), 1.65-1.49 (m, 8H),1.49-1.36 (m, 3H), 1.31 (m, 5H). 251 717.3 ¹H NMR (400 MHz, DMSO-d6) δ8.87 (s, 1H), 8.63 0.04 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.56 (m, 1H),8.16 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 5.25 (m, 1H), 4.65(m, 1H), 3.29-3.17 (m, 2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.17 (m, 2H),2.12-2.01 (m, 2H), 1.89 (m, 1H), 1.67 (m, 1H), 1.58 (m, 6H), 1.27 (s,6H), 1.16-0.93 (m, 8H), 0.45 (m, 1H), 0.26 (m, 1H). 252 717.3 ¹H NMR(400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.63 0.05 (d, J = 1.6 Hz, 1H), 8.61(s, 1H), 8.56 (m, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.50 (m,1H), 5.25 (m, 1H), 4.65 (m, 1H), 3.29-3.17 (m, 2H), 2.75 (m, 1H), 2.60(m, 1H), 2.17 (m, 2H), 2.12-2.01 (m, 2H), 1.89 (m, 1H), 1.67 (m, 1H),1.58 (m, 6H), 1.27 (s, 6H), 1.16-0.93 (m, 8H), 0.45 (m, 1H), 0.26 (m,1H). 253 717.3 ¹H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.63 0.05 (d, J= 1.6 Hz, 1H), 8.61 (s, 1H), 8.56 (m, 1H), 8.16 (d, J = 1.8 Hz, 1H),7.99 (s, 1H), 7.50 (m, 1H), 5.25 (m, 1H), 4.65 (m, 1H), 3.29-3.17 (m,2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.17 (m, 2H), 2.12-2.01 (m, 2H), 1.89(m, 1H), 1.67 (m, 1H), 1.58 (m, 6H), 1.27 (s, 6H), 1.16-0.93 (m, 8H),0.45 (m, 1H), 0.26 (m, 1H). 254 731.3 ¹H NMR (400 MHz, DMSO-d6) δ 8.87(s, 1H), 8.63 0.05 (d, J = 1.7 Hz, 1H), 8.60 (s, 1H), 8.45 (d, J = 7.8Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.98 (s, 1H), 7.50 (m, 1H), 5.26 (m,1H), 4.65 (m, 1H), 4.10-3.93 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 2.50(m, 1H), 2.22-2.12 (m, 2H), 2.07 (m, 3H), 1.89 (m, 1H), 1.66 (m, 1H),1.58 (m, 6H), 1.33-1.19 (m, 6H), 1.17-0.93 (m, 11H), 0.44 (m, 1H), 0.26(m, 1H). 255 715.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.17 (s, 1H), 0.18.74 (s, 1H), 8.70 (s, 1H), 8.35 (m, 1H), 7.77 (s, 1H), 7.60 (d, J = 8.1Hz, 1H), 7.34 (d, J = 6.9 Hz, 1H), 5.30 (m, 1H), 4.22 (m, 1H), 3.60 (m,1H), 3.22 (m, 2H), 3.04-2.82 (m, 4H), 2.79 (m, 2H), 2.72-2.49 (m, 3H),2.27 (m, 3H), 2.25-2.18 (m, 1H), 1.96 (m, 1H), 1.59 (d, J = 6.5 Hz, 6H),1.40 (s, 3H), 1.31 (s, 6H), 1.25-1.18 (m, 1H), 1.06 (t, J = 7.2 Hz, 3H),0.81-0.73 (m, 1H), 0.66-0.54 (m, 1H). 256 753.3 ¹H NMR (400 MHz,DMSO-d6) delta 8.98 (s, 1H), 0.05 8.78-8.59 (m, 3H), 8.50 (s, 1H), 8.03(d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 6.07 (t, J= 57.0 Hz, 1H), 5.28 (p, J = 6.9 Hz, 1H), 4.42 (q, J = 8.1 Hz, 1H), 3.23(t, J = 11.5 Hz, 4H), 3.10 (t, J = 11.0 Hz, 2H), 2.43 (s, 3H), 2.29 (s,3H), 1.79 (s, 4H), 1.70 (d, J = 11.5 Hz, 1H), 1.65-1.55 (m, 9H), 1.52-1.40 (m, 1H), 1.32 (s, 6H), 1.08 (s, 2H), 0.93 (s, 2H). 257 761.3 ¹H NMR(400 MHz, DMSO-J₆) δ 9.24-9.08 (m, 0.1 1H), 8.97 (s, 1H), 8.70 (m, 3H),8.03 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07-5.22 (m, 2H), 4.37-4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m,2H), 2.67 (m, 3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (m, 7H), 1.44 (m,3H), 1.31 (s, 6H), 1.24 (m, 2H), 1.09 (m, 3H), 0.93-0.78 (m, 4H), 0.61(m, 1H). 258 761.3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.24-9.08 (m, 0.09 1H),8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.41(d, J = 6.9 Hz, 1H), 6.07- 5.22 (m, 2H), 4.37-4.18 (m, 1H), 3.63 (m,1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.67 (m, 3H), 2.29 (m, 4H), 1.97 (m,1H), 1.59 (m, 7H), 1.44 (m, 3H), 1.31 (s, 6H), 1.24 (m, 2H), 1.09 (m,3H), 0.93-0.78 (m, 4H), 0.61 (m, 1H). 259 761.3 ¹H NMR (400 MHz,DMSO-d₆) δ 9.24-9.08 (m, 0.09 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d,J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07- 5.22 (m,2H), 4.37-4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.67(m, 3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (m, 7H), 1.44 (m, 3H), 1.31(s, 6H), 1.24 (m, 2H), 1.09 (m, 3H), 0.93-0.78 (m, 4H), 0.61 (m, 1H).260 779.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.11 0.08 (s, 1H),8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.04 (t, J = 56.6 Hz,1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.02 (m, 2H), 2.88 (m,2H), 2.65 (m, 3H), 2.25 (m, 1H), 1.98 (m, 1H), 1.64-1.51 (m, 6H), 1.44(m, 2H), 1.31 (m, 5H), 1.24 (m, 1H), 1.10 (m, 3H), 0.93 (m, 2H), 0.78(m, 1H), 0.62 (m, 1H). 261 779.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.17 (s,1H), 9.11 0.09 (s, 1H), 8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz,1H), 8.10 (d, J = 2.7 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H),6.04 (t, J = 56.6 Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H),3.02 (m, 2H), 2.88 (m, 2H), 2.65 (m, 3H), 2.25 (m, 1H), 1.98 (m, 1H),1.64-1.51 (m, 6H), 1.44 (m, 2H), 1.31 (m, 5H), 1.24 (m, 1H), 1.10 (m,3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.62 (m, 1H). 262 779.3 ¹H NMR (400MHz, DMSO-d6) δ 9.17 (s, 1H), 9.11 0.1 (s, 1H), 8.93 (s, 1H), 8.73 (s,1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.69 (s, 1H),7.50 (d, J = 7.2 Hz, 1H), 6.04 (t, J = 56.6 Hz, 1H), 5.25 (m, 1H), 4.30(m, 1H), 3.64 (m, 1H), 3.02 (m, 2H), 2.88 (m, 2H), 2.65 (m, 3H), 2.25(m, 1H), 1.98 (m, 1H), 1.64-1.51 (m, 6H), 1.44 (m, 2H), 1.31 (m, 5H),1.24 (m, 1H), 1.10 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.62 (m, 1H).263 779.3 ¹H NMR (400 MHz, DMSO-d6) δ 10.07 (bs, 1H), 0.05 9.18 (m, 2H),8.93 (s, 1H), 8.75-8.62 (m, 2H), 8.15- 8.04 (m, 2H), 7.89 (d, J = 1.8Hz, 1H), 7.53 (dd, J = 7.5, 2.1 Hz, 1H), 6.05 (t, J = 56.9 Hz, 1H), 5.26(m, 1H), 4.50 (m, 1H), 3.32 (m, 1H), 3.27-3.07 (m, 4H), 2.72 (m, 1H),1.92-1.68 (m, 5H), 1.69-1.53 (m, 9H), 1.43 (m, 1H), 1.32 (d, J = 5.8 Hz,6H), 1.10 (m, 2H), 0.94 (m, 3H). 264 763.3 ¹H NMR (400 MHz, DMSO-d6) δ9.21 (m, 1H), 9.05 0.2 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.71 (s, 1H),8.61 (s, 1H), 8.07 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.2Hz, 1H), 6.08 (t, J = 57.1 Hz, 1H), 5.28 (m, 1H), 4.33 (m, 1H), 3.22 (m,2H), 2.98-2.85 (m, 4H), 2.65 (m, 2H), 2.34 (m, 3H), 1.84 (m, 2H),1.75-1.62 (m, 3H), 1.59 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.49- 1.39(m, 1H), 1.31 (s, 6H), 1.10-1.05 (m, 2H), 0.95- 0.89 (m, 2H). 265 717.3¹H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.90 0.06 (s, 1H), 8.73 (d, J= 1.7 Hz, 1H), 8.63 (d, J = 7.5 Hz, 2H), 8.10 (s, 1H), 7.71 (d, J = 1.7Hz, 1H), 7.44 (m, 1H), 5.25 (m, 1H), 4.33 (m, 1H), 3.22 (s, 1H), 3.03-2.86 (m, 4H), 2.81 (m, 1H), 2.73-2.60 (m, 1H), 1.86 (m, 2H), 1.69 (m,3H), 1.58 (d, J = 6.5 Hz, 6H), 1.52 (s, 3H), 1.43 (m, 1H), 1.31 (s, 6H),0.69 (m, 2H), 0.55-0.41 (m, 2H). 266 702.4 ¹H NMR (400 MHz, DMSO-d6) δ9.03 (s, 1H), 8.66 0.06 (m, 1H), 8.61 (s, 1H), 8.42-8.38 (m, 1H), 7.90(s, 1H), 7.70-7.60 (m, 2H), 7.45 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 7.8Hz, 1H), 7.17 (d, J = 12.1 Hz, 1H), 6.09 (m, 1H), 5.27 (m, 1H), 4.27 (m,1H), 3.65-3.54 (m, 2H), 3.22 (m, 2H), 2.92 (m, 4H), 2.71-2.58 (m, 3H),2.36 (s, 3H), 1.84 (m, 2H), 1.69 (m, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.51(s, 3H), 1.29 (s, 6H). 267 719.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.16 (s,1H), 8.94 0.1 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 12.0 Hz,1H), 8.47 (d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.71 (m, 1H), 7.44 (m, 1H),5.27 (m, 1H), 4.32 (m, 1H), 4.11- 3.88 (m, 1H), 3.23 (m, 2H), 2.94 (m,4H), 2.67 (m, 2H), 1.85 (m, 2H), 1.70 (m, 3H), 1.59 (d, J = 6.5 Hz, 6H),1.52 (s, 3H), 1.43 (m, 1H), 1.31 (s, 6H), 1.13 (d, J = 6.6 Hz, 6H). 268720.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.79 0.03 (m, 1H), 8.67(d, J = 9.0 Hz, 2H), 7.93 (s, 1H), 7.64 (m, 1H), 7.44-7.35 (m, 3H), 6.11(m, 1H), 5.34- 5.23 (m, 1H), 4.29 (m, 1H), 3.72-3.55 (m, 1H), 3.23 (m,2H), 2.93 (m, 4H), 2.66 (m, 2H), 2.30 (m, , 3H), 1.84 (m, 2H), 1.74-1.36(m, 13H), 1.29 (s, 6H). 269 739.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.04(s, 1H), 0.07 8.82-8.70 (m, 2H), 8.64 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H),7.62 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.1 Hz, 1H), 6.36-5.82 (m, 1H),5.28 (m, 1H), 4.24 (m, 1H), 3.81-3.55 (m, 1H), 3.24-3.10 (m, 2H), 2.90(m, 3H), 2.59 (m, 2H), 2.38-2.19 (m, 3H), 1.93-1.81 (m, 2H), 1.68 (s,3H), 1.58 (d, J = 6.6 Hz, 6H), 1.48 (s, 3H), 1.41 (m, 1H), 1.31 (s, 6H).270 749.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.10 (d, J = 8.3 0.1 Hz, 1H),8.98 (s, 1H), 8.72 (s, 1H), 8.53 (m, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.61(d, J = 8.2 Hz, 1H), 7.44 (m, 1H), 5.33-5.22 (m, 1H), 4.31-4.18 (m, 1H),3.40-3.17 (m, 4H), 3.11 (m, 1H), 3.04-2.90 (m, 1H), 2.78 (m, 1H),2.58-2.51 (m, 1H), 2.49- 2.44 (m, 1H), 1.99-1.78 (m, 3H), 1.62-1.54 (m,8H), 1.50 (s, 3H), 1.31 (s, 6H), 1.16-1.02 (m, 3H), 0.95 (m, 1H),0.65-0.58 (m, 1H), 0.55-0.40 (m, 3H). 271 703.4 ¹H NMR (400 MHz,DMSO-d6) delta 9.06 (s, 1H), 0.06 8.71 (s, 1H), 8.66 (s, 1H), 8.35 (m,1H), 7.76 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.34 (m, 1H),5.28 (m, 1H), 4.23 (m, 1H), 3.22 (m, 4H), 2.98-2.81 (m, 4H), 2.71-2.57(m, 2H), 2.27 (m, 3H), 1.84 (m, 2H), 1.68 (s, 3H), 1.58 (d, J = 6.6 Hz,6H), 1.48 (s, 3H), 1.31 (s, 6H), 1.06 (t, J = 7.2 Hz, 3H). 272 759.3 ¹HNMR (400 MHz, DMSO-d6) delta 9.07 (s, 1H), 0.09 9.04-8.91 (m, 2H), 8.68(s, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.46 (m,1H), 6.10 (tt, J = 55.5, 3.6 Hz, 1H), 5.26 (m, 1H), 4.24 (m, 1H), 3.66(m, 2H), 3.19 (m, 2H), 2.91 (m, 4H), 1.84 (m, 2H), 1.66 (m, 4H), 1.58(d, J = 6.6 Hz, 6H), 1.48 (m, 4H), 1.31 (s, 6H). 273 723.3 ¹H NMR (400MHz, DMSO-d6) delta 9.19 (s, 1H), 0.07 8.99 (s, 1H), 8.72 (s, 1H), 8.54(m, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.43 (m,1H), 5.27 (m, 1H), 4.26 (m, 1H), 3.32-3.10 (m, 4H), 3.10- 2.83 (m, 4H),2.63-2.56 (m, 1H), 1.84 (m, 2H), 1.70 (m, 2H), 1.58 (m, 7H), 1.49 (m,4H), 1.31 (s, 6H), 1.08 (t, J = 7.2 Hz, 3H). 274 725.3 ¹H NMR (400 MHz,DMSO-d6) delta 9.28 (m, 1H), 0.04 8.90 (m, 1H), 8.84 (s, 1H), 8.74 (s,1H), 8.71 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.60 (m, 1H), 6.15 (tt, J= 55.7, 3.8 Hz, 1H), 5.29 (m, 1H), 4.30 (m, 1H), 3.71 (m, 2H), 3.21 (m,2H), 2.99-2.83 (m, 4H), 2.64 (m, 2H), 1.84 (m, 2H), 1.75-1.65 (m, 3H),1.60 (d, J = 6.5 Hz, 6H), 1.50 (s, 3H), 1.45-1.36 (m, 1H), 1.30 (s, 6H).275 738.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.05-8.92 (m, 0.06 3H), 8.66 (s,1H), 8.01 (s, 1H), 7.65 (m, 1H), 7.53- 7.44 (m, 2H), 7.07 (d, J = 7.9Hz, 1H), 6.11 (tt, J = 55.6, 3.7 Hz, 1H), 5.25 (m, 1H), 4.38 (m, 1H),3.21 (m, 2H), 3.05-2.82 (m, 5H), 2.75-2.61 (m, 2H), 1.84 (m, 3H),1.77-1.35 (m, 14H). 276 666.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.03 (s,1H), 0.06 8.60 (s, 1H), 8.34 (s, 1H), 8.24 (m, 1H), 7.89 (s, 1H),7.71-7.63 (m, 2H), 7.47 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H),7.14 (d, J = 12.2 Hz, 1H), 5.27 (m, 1H), 4.29 (m, 1H), 3.22 (m, 2H),2.92 (m, 4H), 2.70- 2.59 (m, 4H), 2.35 (m, 3H), 1.84 (m, 2H), 1.69 (t, J= 14.5 Hz, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.29 (s, 6H),1.05 (t, J = 7.2 Hz, 3H). 277 765.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.05(s, 1H), 0.07 8.81-8.73 (m, 2H), 8.66 (s, 1H), 7.76 (d, J = 2.0 Hz, 1H),7.59 (d, J = 8.2 Hz, 1H), 7.37 (m, 1H), 6.10 (tt, J = 55.8, 3.7 Hz, 1H),5.28 (m, 1H), 4.22 (m, 1H), 3.39- 3.21 (m, 2H), 3.02 (m, 2H), 2.75 (m,1H), 2.53 (m, 5H), 2.28 (m, 3H), 1.87 (m, 3H), 1.58 (m, 6H), 1.48 (s,3H), 1.31 (d, J = 1.2 Hz, 6H), 0.95 (m, 1H), 0.61 (m, 1H), 0.54-0.36 (m,3H). 278 689.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.24 (m, 1H), 0.2 8.80(s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.51 (m, 1H), 8.06 (s, 1H), 7.67(s, 1H), 7.57 (m, 1H), 5.29 (m, 1H), 4.35-4.28 (m, 1H), 3.28 (m, 2H),3.21 (m, 2H), 2.96 (m, 2H), 2.89 (m, 2H), 2.64 (m, 2H), 1.84 (m, 2H),1.70 (m, 4H), 1.60 (d, J = 6.5 Hz, 6H), 1.50 (s, 3H), 1.30 (s, 6H), 1.11(t, J = 7.2 Hz, 3H). 279 729.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.08 (m,1H), 0.1 8.72 (s, 1H), 8.35 (m, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.60 (d,J = 8.2 Hz, 1H), 7.35 (d, J = 6.9 Hz, 1H), 5.29 (m, 1H), 4.22 (m, 1H),3.38-3.14 (m, 3H), 3.13- 3.04 (m, 1H), 2.95 (m, 1H), 2.77 (m, 1H), 2.28(m, 3H), 1.99-1.77 (m, 4H), 1.59-1.56 (m, 6H), 1.49 (s, 3H), 1.31 (s,6H), 1.06 (t, J = 7.1 Hz, 3H), 0.65-0.58 (m, 1H), 0.52-0.38 (m, 3H). 280751.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.20 (m, 1H), 0.05 9.10 (s, 1H),8.80 (s, 1H), 8.71 (s, 2H), 8.06 (s, 1H), 7.69 (s, 1H), 7.54 (m, 1H),6.05 (t, J = 56.7 Hz, 1H), 5.28 (m, 1H), 4.29 (m, 1H), 3.21 (m, 2H),2.95 (m, 4H), 2.65 (m, 2H), 1.85 (m, 2H), 1.77-1.64 (m, 4H), 1.60 (d, J= 6.7 Hz, 6H), 1.50 (s, 3H), 1.30 (s, 6H), 1.11 (m, 2H), 0.95 (m, 2H).281 691.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.04 (s, 1H), 0.07 8.89 (s,1H), 8.74 (d, J = 1.7 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J = 4.7 Hz, 1H),8.10 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 7.1 Hz, 1H), 5.25(m, 1H), 4.40- 4.22 (m, 1H), 3.23 (m, 2H), 2.95 (m, 4H), 2.75 (m, 3H),2.72-2.59 (m, 1H), 2.41-2.28 (m, 1H), 1.94- 1.76 (m, 2H), 1.69 (m, 3H),1.59 (s, 3H), 1.52 (m, 4H), 1.31 (s, 6H). 282 767.3 ¹H NMR (400 MHz,DMSO-d6) delta 9.13 (m, 1H), 0.1 9.02 (m, 1H), 8.99 (s, 1H), 8.73 (d, J= 1.7 Hz, 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H),7.49 (m, 1H), 6.13 (tt, J = 55.6, 3.7 Hz, 1H), 5.27 (m, 1H), 4.29 (m,1H), 3.67 (m, 2H), 3.39-3.24 (m, 2H), 3.19-3.10 (m, 1H), 3.03-2.92 (m,1H), 2.87-2.79 (m, 1H), 2.68-2.58 (m, 2H), 2.53-2.45 (m, 1H), 1.98-1.77(m, 3H), 1.59 (m, 6H), 1.52 (s, 3H), 1.31 (s, 6H), 0.96 (m, 1H),0.66-0.59 (m, 1H), 0.54-0.40 (m, 3H). 283 731.3 ¹H NMR (400 MHz,DMSO-d6) delta 9.10 (m, 1H), 0.09 8.93 (s, 1H), 8.74 (d, J = 1.7 Hz,1H), 8.70 (s, 1H), 8.57 (m, 1H), 8.09 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H),7.45 (m, 1H), 5.26 (m, 1H), 4.30 (m, 1H), 3.39-3.20 (m, 4H), 3.19-3.10(m, 1H), 3.04-2.92 (m, 1H), 2.82 (m, 1H), 2.68-2.58 (m, 2H), 2.50 (m,1H), 1.98- 1.80 (m, 3H), 1.58 (m, 6H), 1.52 (s, 3H), 1.31 (s, 6H), 1.09(t, J = 7.2 Hz, 3H), 0.99-0.91 (m, 1H), 0.66-0.59 (m, 1H), 0.54-0.41 (m,3H). 284 747.4 ¹H NMR (400 MHz, DMSO-d6) delta 9.00 (s, 1H), 0.1 8.80(m, 1H), 8.76-8.67 (m, 2H), 8.60 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 1.8Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 6.33-5.94 (m, 1H), 5.27 (m, 1H),4.40-4.16 (m, 1H), 3.76-3.57 (m, 1H), 3.22-3.07 (m, 1H), 2.98 (m, 1H),2.81 (m, 1H), 2.72-2.59 (m, 2H), 2.32 (m, 3H), 1.90 (m, 4H), 1.70-1.40(m, 10H), 1.31 (s, 6H), 0.96 (m, 1H), 0.62 (m, 2H), 0.58-0.40 (m, 2H).285 711.4 ¹H NMR (400 MHz, DMSO-d6) δ 9.27-9.06 (m, 0.1 1H), 8.86-8.64(m, 3H), 8.39 (m, 1H), 8.02 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.37 (m,1H), 5.76 (m, 1H), 5.30 (m, 1H), 4.29 (m, 1H), 3.43-3.19 (m, 4H), 3.15(m, 1H), 2.99 (m, 1H), 2.83 (m, 1H), 2.65 (m, 2H), 2.30 (m, 3H),1.99-1.79 (m, 3H), 1.67-1.41 (m, 9H), 1.31 (s, 6H), 1.08 (t, J = 7.2 Hz,3H), 0.96 (m, 1H), 0.62 (m, 1H), 0.54-0.33 (m, 2H). 286 705.3 ¹H NMR(400 MHz, DMSO-d6) delta 9.12 (s, 1H), 0.1 8.92 (s, 1H), 8.74 (d, J =1.7 Hz, 1H), 8.67 (s, 1H), 8.57 (m, 1H), 8.10 (d, J = 2.9 Hz, 1H), 7.71(d, J = 1.8 Hz, 1H), 7.45 (m, 1H), 5.26 (m, 1H), 4.32 (m, 1H), 3.34-3.14(m, 4H), 2.95 (m, 4H), 2.67 (m, 2H), 1.85 (m, 2H), 1.69 (t, J = 13.8 Hz,3H), 1.64-1.38 (m, 9H), 1.30 (m, 5H), 1.09 (t, J = 7.2 Hz, 3H). 287740.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.13 (s, 1H), 0.08 9.00 (m, 1H),8.94 (s, 1H), 8.66 (s, 1H), 8.00 (s, 1H), 7.66 (m, 1H), 7.48 (m, 1H),7.43 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 6.11 (tt, J = 55.6,3.7 Hz, 1H), 5.31-5.20 (m, 1H), 4.35-4.25 (m, 1H), 3.66 (m, 2H), 3.22(m, 2H), 3.06-2.82 (m, 4H), 2.65 (m, 2H), 1.85 (m, 3H), 1.69 (m, 3H),1.58 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.29 (s, 6H). 288 704.3 ¹H NMR(400 MHz, DMSO-d6) delta 9.12 (s, 1H), 0.08 8.89 (s, 1H), 8.66 (s, 1H),8.56 (m, 1H), 8.00 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 7.44 (d, J = 1.4Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 5.25 (m, 1H), 4.29 (m, 1H), 3.23 (m,4H), 3.06-2.83 (m, 5H), 2.64 (m, 2H), 1.85 (m, 2H), 1.69 (m, 3H), 1.58(d, J = 6.6 Hz, 6H), 1.52 (s, 3H), 1.29 (s, 6H), 1.07 (t, J = 7.2 Hz,3H). 289 722.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.13 (d, J = 0.07 10.2Hz, 1H), 8.90 (m, 1H), 8.68 (d, J = 2.2 Hz, 2H), 7.97 (s, 1H), 7.68 (m,2H), 7.56 (d, J = 10.9 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.38 (d, J =7.8 Hz, 1H), 6.09 (tt, J = 55.8, 3.8 Hz, 1H), 5.26 (m, 1H), 4.30 (m,1H), 3.65 (m, 2H), 3.22 (m, 2H), 3.03-2.83 (m, 5H), 2.62 (m, 2H), 1.85(m, 2H), 1.69 (m, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.52 (s, 3H), 1.29 (s,6H). 290 686.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.15 (d, J = 0.07 10.7Hz, 1H), 8.68 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.46 (m, 1H), 7.97 (s,1H), 7.73-7.67 (m, 2H), 7.53 (d, J = 10.9 Hz, 1H), 7.46 (d, J = 1.5 Hz,1H), 7.38 (d, J = 7.8 Hz, 1H), 5.26 (m, 1H), 4.29 (m, 1H), 3.29- 3.17(m, 4H), 2.93 (m, 5H), 2.63 (m, 2H), 1.85 (m, 2H), 1.68 (m, 3H), 1.58(d, J = 6.6 Hz, 6H), 1.53 (s, 3H), 1.29 (s, 6H), 1.07 (t, J = 7.2 Hz,3H). 291 785.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.15 (s, 1H), 0.08 9.12(s, 1H), 8.99 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.1 Hz,1H), 7.48 (d, J = 7.2 Hz, 1H), 6.00 (t, J = 56.7 Hz, 1H), 5.27 (m, 1H),4.25 (m, 1H), 3.19 (m, 2H), 2.92 (m, 4H), 2.60-2.53 (m, 2H), 1.84 (m,2H), 1.75-1.63 (m, 2H), 1.58 (d, J = 6.5 Hz, 6H), 1.48 (s, 3H), 1.31 (s,6H), 1.09 (m, 2H), 0.91 (m, 2H). 292 748.3 ¹H NMR (400 MHz, DMSO-d6)delta 9.06 (s, 1H), 0.07 8.98 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.00(s, 1H), 7.66 (m, 1H), 7.49 (m, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.39 (d,J = 7.8 Hz, 1H), 5.24 (m, 1H), 4.46 (m, 2H), 4.29 (m, 1H), 3.23 (d, J =11.6 Hz, 2H), 2.94 (m, 5H), 2.65 (m, 2H), 1.85 (m, 2H), 1.69 (m, 3H),1.57 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.30 (s, 6H), 0.97-0.74 (m, 4H).293 730.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.11 (s, 1H), 0.05 8.88 (s,1H), 8.70-8.59 (m, 2H), 7.96 (s, 1H), 7.69 (m, 2H), 7.52 (d, J = 10.8Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 5.26 (m,1H), 4.47 (d, J = 49.1 Hz, 2H), 4.30 (m, 1H), 3.22 (m, 2H), 2.93 (m,5H), 2.63 (m, 2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.58 (d, J = 6.5 Hz, 6H),1.53 (s, 3H), 1.43 (m, 1H), 1.29 (s, 6H), 0.89 (m, 2H), 0.80 (m, 2H).294 748.3 ¹H NMR (400 MHz, DMSO-d6) delta 9.07 (m, 2H), 0.08 8.69-8.58(m, 2H), 7.97 (s, 1H), 7.73-7.66 (m, 2H), 7.54 (d, J = 10.9 Hz, 1H),7.46 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.04 (t, J = 57.0Hz, 1H), 5.32-5.19 (m, 1H), 4.30 (m, 1H), 3.22 (m, 3H), 2.93 (m, 5H),2.64 (m, 2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.58 (d, J = 6.6 Hz, 6H), 1.53(s, 3H), 1.29 (s, 6H), 1.12-1.05 (m, 2H), 0.89 (m, 2H). 295 728.4 ¹H NMR(400 MHz, DMSO-d6) δ 9.02 (m, 1H), 8.85 0.1 (s, 1H), 8.77 (s, 1H), 8.50(s, 1H), 7.82 (s, 1H), 7.67 (m, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38 (d,J = 7.8 Hz, 1H), 7.28 (d, J = 1.4 Hz, 1H), 7.19 (d, J = 11.9 Hz, 1H),6.09 (t, J = 57.2 Hz, 1H), 5.31 (m, 1H), 3.68 (m, 1H), 3.34 (m, 2H),2.80-2.56 (m, 6H), 2.39 (s, 3H), 1.82 (m, 2H), 1.70 (m, 1H), 1.60 (m,6H), 1.56-1.48 (m, 1H), 1.45 (s, 3H), 1.37 (m, 1H), 1.32-1.16 (m, 8H),1.12-1.05 (m, 2H), 0.90 (m, 2H). 296 766.3 ¹H NMR (400 MHz, DMSO-d6) δ9.17 (s, 1H), 8.99 0.1 (d, J = 9.4 Hz, 1H), 8.90 (s, 1H), 8.61 (s, 1H),7.95 (s, 1H), 7.68 (m, 1H), 7.45-7.34 (m, 2H), 7.27 (m, 1H), 6.03 (t, J= 56.7 Hz, 1H), 5.23 (m, 1H), 3.35 (m, 3H), 2.74 (m, 4H), 2.68-2.58 (m,2H), 1.82 (m, 2H), 1.71 (m, 1H), 1.58 (m, 6H), 1.53-1.45 (m, 5H), 1.28(s, 6H), 1.24 (m, 1H), 1.15-1.07 (m, 2H), 0.93 (m, 2H). 297 767.3 ¹H NMR(400 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.10 0.2 (d, J = 9.7 Hz, 1H), 8.94(s, 1H), 8.79 (m, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.51 (m, 1H),7.45-7.38 (m, 1H), 6.05 (t, J = 56.7 Hz, 1H), 5.25 (m, 1H), 3.70 (m,1H), 3.37 (m, 2H), 2.84-2.60 (m, 7H), 1.83 (m, 2H), 1.71-1.59 (m, 7H),1.54 (m, 1H), 1.48 (s, 3H), 1.40 (m, 1H), 1.30 (s, 6H), 1.16-1.08 (m,2H), 0.95 (m, 2H).

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated.

1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein: one of R¹ and R²is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the other of R¹ and R² is H,halogen, or C₁₋₆ alkyl, wherein each C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH and halogen,or R¹ and R² together with the carbon to which they are attached form aC₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic heterocyclylhaving 1 or 2 heteroatoms independently selected from N, O, and S,wherein the C₃₋₇ monocyclic cycloalkyl and the 4-6 membered monocyclicheterocyclyl are each optionally substituted with one R¹¹ and are eachoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, or R¹ and R² together form═O; R¹¹ is i) 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy, ii) —S(O)₂C₁₋₆ alkyl, iii) —S(O)₂C₃₋₇ monocycliccycloalkyl, iv) C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl, or v) —C(O)R²¹; R²¹ is i) H, ii) C₃₋₇ monocyclicor bridged bicyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy, iii) 4-6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iv)5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independentlyselected from N, O, and S, wherein the 5-6 membered monocyclicheteroaryl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, v) —NH₂,vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally substitutedwith 1-3 groups independently selected from —CN, —OH, halogen, and C₁₋₃alkoxy, vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same ordifferent and wherein each C₁₋₆ alkyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy,viii) C₁₋₆ alkoxy optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl,or ix) C₁₋₆ alkyl optionally substituted with 1-3 groups independentlyselected from a) —CN, b) —OH, c) halogen, d) C₁₋₃ alkoxy, e) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, f) 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy, and g) —OC(O)C₁₋₆ alkyl optionally substituted with one—OH; R³ and R¹³ are each H, or R³ and R¹³ together form ═O; L¹ is acyclobutylene optionally substituted with 1-6 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; X is —NR¹⁵R¹⁶,wherein R¹⁵ and R¹⁶ are independently i) H, ii) C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iii) 4-7 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iv) —C(O)C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or v) C₁₋₆ alkyloptionally substituted with 1-6 groups independently selected from a)—CN, b) —OH, c) halogen, d) C₁₋₃ alkoxy, e) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and f) 5-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; or X is a 4-10 membered monocyclic,fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S, wherein the 4-10membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl is optionally substituted with 1-5 R¹⁸; each R¹⁸ isindependently i) —CN, ii) a halogen, iii) —OH, iv) C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, v) C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, vi) —COOH, or vii)—C(O)N(R²²)₂, wherein each R²² is independently H or C₁₋₆ alkyl; X¹ is Nor CR¹⁷; R⁴, R⁵, R⁶, R¹⁰ and R¹⁷ are each independently H, halogen, C₁₋₃alkyl, or C₁₋₃ alkoxy; R⁷ is i) H, ii) C₁₋₆ alkyl optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkoxy,and C₃₋₇ monocyclic cycloalkyl, or iii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; Z is —O—, —C(R⁸)₂—, or —NR⁸—; eachR⁸ is independently H or C₁₋₃ alkyl; R^(9a), R^(9b), R^(9c), R^(9d), andR^(9e) are independently i) H, ii) halogen, iii) C₁₋₆ alkoxy optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl, iv) —NH₂, v) —NH(C₁₋₆alkyl), wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy, vi) —N(C₁₋₆alkyl)₂, wherein each C₁₋₆ alkyl can be the same or different, andwherein each C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy, vii)—P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same ordifferent, and wherein each C₁₋₆ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy,viii) —S(O)₂C₁₋₆ alkyl, ix) —S(O)₂N(R²³)₂, wherein each R²³ isindependently H or C₁₋₆ alkyl, x) C₁₋₆ alkyl optionally substituted with1-3 groups independently selected from a) —OH, b) halogen, c) C₁₋₃alkoxy, d) C₃₋₇ monocyclic cycloalkyl, e) 5-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from oxo and C₁₋₃alkyl, and f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl, xi)C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,xii) 5-6 membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from N, O, and S, wherein the 5-6 memberedmonocyclic heteroaryl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,xiii) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy, xiv) —COOH, xv) —C(O)N(R¹⁹)₂, or xvi) —C₁₋₃ alkylC(O)N(R¹⁹)₂,wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is—C(O)N(R¹⁹)₂ or —C₁₋₃ alkylC(O)N(R¹⁹)₂; and each R¹⁹ is independently i)H, ii) —S(O)₂C₁₋₆ alkyl, iii) C₁₋₆ alkyl optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl, iv) C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-6 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy, or v) 4-6 membered monocyclicheterocyclyl having 1-3 heteroatoms independently selected from N, O,and S, wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-6 groups independently selected from —CN, —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.
 2. The compound of claim 1,wherein the compound is of Formula II:

or a pharmaceutically acceptable salt thereof, wherein each R¹² isindependently —OH, halogen, C₁₋₃ alkyl, or C₁₋₃ alkoxy; and n is 0, 1,2, 3, or
 4. 3. The compound of claim 2, wherein the compound is ofFormula IIa:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein the compound has a Formula IIb:

or the pharmaceutically acceptable salt thereof.
 5. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴, R⁵,R⁶, and R¹⁰ are H.
 6. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein n is 0, 1, or
 2. 7. The compound ofclaim 1, wherein the compound is of Formula III:

or a pharmaceutically acceptable salt thereof, wherein: one of R¹ and R²is —OH, halogen, or C₁₋₃ alkyl, and the other of R¹ and R² is halogen orC₁₋₃ alkyl, or R¹ and R² together with the carbon to which they areattached form a 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with one R¹¹and optionally substituted with 1-3 groups independently selected from—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, ii) —S(O)₂C₁₋₃ alkyl,iii) —S(O)₂C₃₋₅ monocyclic cycloalkyl, iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, or v) —C(O)R²¹;R²¹ is i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy, ii) 4-6 membered monocyclic heterocyclylhaving 1 or 2 heteroatoms independently selected from N, O, and S,wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iii) C₁₋₆ alkoxy optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl, or iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from a) —CN, b) —OH,c) halogen, and d) C₁₋₃ alkoxy, R³ and R¹³ are each H, or R³ and R¹³together form ═O; n is 0 or 1; R¹² is C₁₋₃ alkyl; X is —NR¹⁵R¹⁶, whereinR¹⁵ and R¹⁶ are independently i) H, ii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iii) 4-7 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-3 groups independently selectedfrom —CN, —OH, halogen, and C₁₋₃ alkoxy, or v) C₁₋₆ alkyl optionallysubstituted with 1-6 groups independently selected from a) —OH, b)halogen, and c) C₁₋₃ alkoxy; or X is a 4-10 membered monocyclic, fusedbicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S, wherein the 4-10membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl is optionally substituted with 1-5 R¹⁸; each R¹⁸ isindependently i) a halogen, ii) —OH, or iii) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; X¹ is N or CH; R⁷ is i)C₁₋₆ alkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, or ii)C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; Zis —O— or NH; R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) areindependently i) H, ii) halogen, iii) C₁₋₆ alkoxy optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl,and C₃₋₇ monocyclic cycloalkyl, iv) C₁₋₆ alkyl optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkoxy,and C₃₋₇ monocyclic cycloalkyl, v) C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy, or vi) —C(O)N(R¹⁹)₂, wherein one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂; each R¹⁹ isindependently i) H, ii) C₁₋₆ alkyl optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl, or iii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-6 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy.
 8. The compound of claim 1, wherein thecompound is of Formula IIIa:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R³ and R¹³together form ═O.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X¹ is CH.
 11. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein X¹ is N.
 12. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹² is C₁₋₃ alkyl.
 13. (canceled)
 14. (canceled)
 15. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Z is NH.
 16. The compound of claim 1, wherein the compound is ofFormula IV:

or a pharmaceutically acceptable salt thereof, wherein: one of R¹ and R²is —OH, halogen, or C₁₋₃ alkyl, and the other of R¹ and R² is halogen orC₁₋₃ alkyl, or R¹ and R² together with the carbon to which they areattached form a 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with one R¹¹and optionally substituted with 1-3 groups independently selected from—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, ii) —S(O)₂C₁₋₃ alkyl,iii) —S(O)₂C₃₋₄ monocyclic cycloalkyl, iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl. or v) —C(O)R²¹;R²¹ is i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy, ii) 4-6 membered monocyclic heterocyclylhaving 1 or 2 heteroatoms independently selected from N, O, and S,wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iii) C₁₋₆ alkoxy optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl, or iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from a) —CN, b) —OH,c) halogen, and d) C₁₋₃ alkoxy, X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ areindependently i) H, ii) C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy, iii) 4-7 membered monocyclic heterocyclylhaving 1 or 2 heteroatoms independently selected from N, O, and S,wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-3 groups independently selectedfrom —CN, —OH, halogen, and C₁₋₃ alkoxy, or v) C₁₋₆ alkyl optionallysubstituted with 1-6 groups independently selected from a) —OH, b)halogen, and c) C₁₋₃ alkoxy; or X is a 4-10 membered monocyclic, fusedbicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S, wherein the 4-10membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl is optionally substituted with 1-5 R¹⁸; each R¹⁸ isindependently i) a halogen, ii) —OH, or iii) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; R⁷ is i) C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, or ii) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy;R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently i) H, ii)halogen, iii) C₁₋₆ alkoxy optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇monocyclic cycloalkyl, iv) C₁₋₆ alkyl optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl, v) C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy, or vi) —C(O)N(R¹⁹)₂, wherein one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂; each R¹⁹ isindependently i) H, ii) C₁₋₆ alkyl optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl, or iii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-6 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy.
 17. The compound of claim 1, wherein thecompound has a Formula IVa:

or the pharmaceutically acceptable salt thereof.
 18. The compound ofclaim 1, wherein the compound has a Formula IVb:

or the pharmaceutically acceptable salt thereof.
 19. The compound ofclaim 1, wherein the compound has a Formula IVc:

or the pharmaceutically acceptable salt thereof. 20-49. (canceled) 50.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein one of R¹ and R² is —OH, fluoro, methyl, or ethyl and the otherof one of R¹ and R² is fluoro, methyl, or ethyl.
 51. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ andR² are both fluoro, methyl, or ethyl.
 52. (canceled)
 53. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein one ormore of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently: i)H, ii) halogen, iii) C₁₋₃ alkyl optionally substituted with 1-3 groupsindependently selected from —OH and halogen, iv) —OCH₃ optionallysubstituted with 1-3 halogen groups, v) cyclopropyl, or vi)—C(O)N(R¹⁹)₂, and wherein one or more of R^(9a), R^(9b), R^(9c), R^(9d),and R^(9e) is —C(O)N(R¹⁹)₂. 54-56. (canceled)
 57. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) are independently H, fluoro,chloro, methyl, ethyl, or —C(O)N(R¹⁹)₂, and wherein one or more ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is —C(O)N(R¹⁹)₂. 58.(canceled)
 59. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R^(9a), R^(9b), R^(9c), and R^(9e) areindependently H, fluoro, chloro, methyl, or ethyl and R^(9d) is—C(O)N(R¹⁹)₂; wherein each R¹⁹ is independently H or cyclopropyl,wherein the cyclopropyl is optionally substituted with a methyl, andwherein the methyl is optionally substituted with 1-3 groupsindependently selected from fluoro and —OCH₃.
 60. The compound of claim59, or a pharmaceutically acceptable salt thereof, wherein R^(9a),R^(9b), R^(9c), and R^(9e) are independently H, fluoro, chloro, methyl,or ethyl and R^(9d) is —C(O)N(R¹⁹)₂; wherein each R¹⁹ is independently Hor cyclopropyl, wherein the cyclopropyl is optionally substituted with amethyl, and wherein the methyl is optionally substituted with 1-3 fluorogroups.
 61. The compound of claim 60, or a pharmaceutically acceptablesalt thereof, wherein R^(9a), R^(9b), R^(9c), and R^(9e) areindependently H, fluoro, chloro, methyl, or ethyl and R^(9d) is—C(O)NH(R¹⁹); wherein R¹⁹ is cyclopropyl optionally substituted with amethyl, and wherein the methyl is optionally substituted with 1-3 fluorogroups.
 62. The compound of claim 61, or a pharmaceutically acceptablesalt thereof, wherein R^(9a), R^(9b), R^(9c), and R^(9e) areindependently H, fluoro, or chloro and R^(9d) is —C(O)NH(R¹⁹); whereinR¹⁹ is cyclopropyl optionally substituted with a methyl, and wherein themethyl is optionally substituted with 1-3 fluoro groups.
 63. Thecompound of claim 62, or a pharmaceutically acceptable salt thereof,wherein R^(9a), R^(9b), and R^(9c) are independently fluoro or chloro,R^(9e) is H, and R^(9d) is —C(O)NH(R¹⁹); wherein R¹⁹ is cyclopropyloptionally substituted with a methyl, wherein the methyl is optionallysubstituted with 1-3 fluoro groups.
 64. The compound of claim 63, or apharmaceutically acceptable salt thereof, wherein R^(9d) is F


65. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(9a) is H or fluoro.
 66. The compound of claim 65, ora pharmaceutically acceptable salt thereof, wherein R^(9b) is H ormethyl.
 67. The compound of claim 66, or a pharmaceutically acceptablesalt thereof, wherein R^(9c) is H, fluoro, chloro, methyl, ethyl, —CF₃,—OCF₃, or cyclopropyl.
 68. The compound of claim 67, or apharmaceutically acceptable salt thereof, wherein R^(9c) is methyl. 69.The compound of claim 68, or a pharmaceutically acceptable salt thereof,wherein R^(9e) is H.
 70. The compound of claim 69, or a pharmaceuticallyacceptable salt thereof, wherein R^(9d) is —C(O)N(R¹⁹)₂.
 71. (canceled)72. (canceled)
 73. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹⁹ is independently: i) H, ii)methyl, iii) ethyl optionally substituted with 1 or 2 groupsindependently selected from —OH, fluoro, and —OCH₃, iv) n-propyloptionally substituted with 1 or 2 groups independently selected fromfluoro and —OCH₃, v) isopropyl optionally substituted with 1 or 2 fluorogroups, vi) n-butyl, vii) isobutyl optionally substituted with 1 or 2fluoro groups, viii) sec-butyl, ix) tert-butyl, x) cyclopropyloptionally substituted with a methyl, wherein the methyl is optionallysubstituted with 1-3 groups independently selected from fluoro and—OCH₃, or xi) cyclobutyl. 74-77. (canceled)
 78. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁷ is methyl,ethyl, isopropyl, sec-butyl, or cyclopropyl, wherein the cyclopropyl isoptionally substituted with one methyl. 79-93. (canceled)
 94. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein X is a 4-8 membered monocyclic, fused bicyclic, bridgedbicyclic, or spirocyclic heterocyclyl having 1 or 2 heteroatomsindependently selected from N and O, wherein the 4-8 memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl is optionally substituted with 1-5 R¹⁸.
 95. (canceled) 96.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein X is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl, eachof which is optionally substituted with 1-5 R¹⁸. 97-102. (canceled) 103.The compound of claim 94, or a pharmaceutically acceptable salt thereof,wherein X is:

each of which is optionally substituted with 1-5 R¹⁸.
 104. (canceled)105. The compound of claim 103, or a pharmaceutically acceptable saltthereof, wherein X is:

each of which is optionally substituted with 1-4 R¹⁸.
 106. (canceled)107. (canceled)
 108. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R¹⁸ is independently: i) —OH, ii)fluoro, or iii) C₁₋₃ alkyl optionally substituted with 1-3 groupsindependently selected from —OH and halogen. 109-127. (canceled)
 128. Apharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.
 129. The pharmaceutical composition ofclaim 128, further comprising one or more additional therapeutic agents,or a pharmaceutically acceptable salt thereof. 130-134. (canceled) 135.A method of inhibiting hematopoietic progenitor kinase 1 (HPK1) activityin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 136. (canceled)
 137. A methodof increasing T-cell activation in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof. 138.A method of treating cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 1, or a pharmaceutically acceptable salt thereof.139-183. (canceled)